Revisiting Species Distribution and Antifungal Susceptibility of Candida Bloodstream Isolates from

14 Pages·2017·1.2 MB·English

Journal of
Fungi
Review
Revisiting Species Distribution and Antifungal
Susceptibility of Candida Bloodstream Isolates from
Latin American Medical Centers
DanielArchimedesdaMatta,AnaCarolinaRemondiSouzaandArnaldoLopesColombo*
LaboratórioEspecialdeMicologia,DisciplinadeInfectologia,EscolaPaulistadeMedicina,
UniversidadeFederaldeSãoPaulo,SãoPaulo,SP04039-032,Brazil;[email protected](D.A.d.M.);
[email protected](A.C.R.S.)
* Correspondence:[email protected];Tel.:[phone]
AcademicEditor:DavidS.Perlin
Received:24March2017;Accepted:12May2017;Published:17May2017
Abstract: Theepidemiologyofcandidemiavariesgeographically,andthereisstillscarcedataonthe
epidemiologyofcandidemiainLatinAmerica(LA).Afterextensiverevisionofmedicalliterature,we
foundreliableandrobustinformationonthemicrobiologicalaspectsofcandidemiainpatientsfrom
11outof21medicalcentersfromLAcountriesand1outof20fromCaribbeancountries/territories.
Basedon40papersattendingoursearchstrategy,wenotedthatC.albicansremainsthemostcommon
speciescausingcandidemiainourregion,followedbyC.parapsilosisandC.tropicalis. InArgentina,
Brazil,andColombia,atrendtowardsanincreaseinfrequencyofC.glabratacandidemiawasobserved.
Althoughresistanceratestofluconazoleisunder3%,therewasaslightincreaseintheresistance
ratestoC.albicans,C.parapsilosisandC.tropicalisisolates. Echinocandinresistancehasbeenreported
inafewsurveys,butnosinglestudyconfirmedtheresistantphenotypereportedbyusingmolecular
methods. Wehighlighttheimportanceofconductingcontinuoussurveillancestudiestoidentifynew
trendsintermsofspeciesdistributionofCandidaandantifungalresistancerelatedtoepisodesof
candidemiainLA.ThisinformationiscriticalforhelpingclinicianstopreventandcontrolCandida
bloodstreaminfectionsintheirmedicalcenters.
Keywords: candidemia; Candida spp.; nosocomial infection; infections acquired in a healthcare
setting;antifungalresistance;opportunisticinfections
1. Introduction
Fungihasbeenincreasinglyrecognizedasmajoragentsofnosocomialinfectionsincontemporary
medicine, with emphasis on Candida spp., that accounts for the majority of invasive fungal
infectionsassociatedinhealthcarefacilities. Indeed,besidesbeinghighlyprevalentinLatinAmerica
countries,candidemiaisassociatedwithhighmorbidityandmortalityrates,especiallyincriticallyill
patients[1–7].
Theepidemiologyofcandidemiavariesgeographically,and,althoughC.albicansisstillconsidered
themostcommoncauseofcandidemia,thereisaconcernwiththeincreasingratesofinvasiveinfections
duetoCandidanon-albicans(CNA)speciesindifferentpartsoftheworld[7–10]. Thereasonsforthe
differencesinspeciesdistributionandfortheemergenceofCNAspeciesarenotfullyunderstood.
However,thereseemstobeanassociationwithacombinationofvariablesrelatedtohostunderlying
conditions and medical interventions, including different practices of antifungal prophylaxis and
resourcesavailableforpreventionofhealthcareassociatedinfections[5,9,11–17].
RecognitionoftheimportanceofCandidainfectionshasledtoasignificantincreaseintheuse
ofantifungalagentsinregimentsofprophylaxisandempiricaltherapy,resultingintheemergence
J.Fungi2017,3,24;doi:10.3390/jof3020024 www.mdpi.com/journal/jof
J.Fungi2017,3,24 2of14
ofresistantclinicalisolates,particularlyagainsttriazolesandechinocandins[18,19]. Inthisscenario,
therecentemergenceoffluconazoleresistanceamongisolatesthatareusuallyprimarilysensitiveto
thisdrug,includingC.parapsilosisandC.tropicalisstrains,isworthmentioning[8,20–24]. Regarding
toechinocandins,thoughresistanceisstillconsidereduncommon,occurrenceofisolateswithlower
susceptibilitytothistherapeuticclasshasbeenincreasinglyreported,particularlyamongC.glabrata
isolates[19,25–27].
TheawarenessoflocalepidemiologyandantifungalsusceptibilityprofileofCandidainfections
in different medical centers has major relevance in terms of guiding clinicians in optimizing their
strategyforpreventionandtreatmentofsuchfungalinfections. Thisreviewattemptstoprovidea
betterunderstandingofthelandscapeofspeciesdistributionandantifungalresistanceratesamong
Candida bloodstream isolates obtained from patients admitted in Latin American and Caribbean
medicalcenters.
2. Methods
Oursearchstrategyfortheliteraturereviewwasbasedonextensiverevisionofpublicationslisted
at PubMed, Scientific Electronic Library Online (SciELO), and MEDLINE bibliographic databases
alongtheperiodbetween1997and2016,irrespectiveoflanguageandcountryofpublication. Papers
wereretrievedusingthefollowingkeywords: candidemia,fungemia,Candidabloodstreaminfection,
invasivecandidiasis,Candidaspeciesdistribution,antifungalsusceptibility,andantifungalresistance.
Foreachofthesesubjects,wealsonarrowedoursearchbyaddingthecontinentandcountryincluding
thefollowing: CentralAmerica,LatinAmerica,SouthAmerica,Caribbean,Argentina,Bolivia,Brazil,
Chile,Colombia,CostaRica,Cuba,DominicanRepublic,Haiti,Honduras,Jamaica,Mexico,Panama,
Peru, Puerto Rico, Uruguay, and Venezuela. Papers were included in our analysis only if their
methodologyandresultsmatchedthefollowingcriteria: (i)Candidaisolateswereidentifiedatspecies
levelbyareliableandaccuratephenotypicormolecularmethod;(ii)availabilityofdatarelatedto
at least 50 Candida bloodstream isolates sequentially collected from different patients admitted in
tertiaryhospitalsalongtheperiodofstudy;(iii)informationregardingantifungalsusceptibilityof
Candidaspp. generatedbyTheEuropeanCommitteeonAntimicrobialSusceptibilityTesting(EUCAST)
orClinicalLaboratoryStandardInstitute(CLSI)microbrothmethods. Ratesofresistancetotriazoles
andechinocandinsreflectthebreakpointsavailableatthetimewhenthestudywaspublished. Papers
addressingidentificationandsusceptibilitytestsofworldwidecollectionsofCandidaisolateswere
consideredonlyifisolateswereobtainedfrompatientswithcandidemiaanddatafromLatinAmerican
or Caribbean countries were addressed separately. For antifungal susceptibility results, we only
considered studies that tested at least 60% of all original collections of Candida strains originally
selectedforthestudy.
3. Results
Weidentified40studiesthatcontainedourinclusioncriteriaprovidingdataofspeciesdistribution
and antifungal susceptibility of Candida strains related to episodes of candidemia documented in
LatinAmericanandCaribbeanmedicalcenters.
Intermsofgeographicorigin,22paperswerefromBrazil,4fromArgentina,4fromColombia,
2fromMexico, and1eachrepresentingthefollowingcountries: CostaRica, Peru, Venezuela, and
Puerto Rico (Caribbean region). Of note, Puerto Rico is an unincorporated territory of the United
StatesofAmerica(USA),locatedintheCaribbean.Inadditionto36studiesreportingdataofsingle
countries, we also evaluated results provided by 4 multicenter studies that tested Candida spp.
bloodstream isolates from multiple Latin American countries including Argentina, Brazil, Chile,
Colombia,CostaRica,Ecuador,Honduras,Mexico,Peru,Uruguay,andVenezuela.Inthisscenario,
weidentifiedpaperscharacterizingtheetiologicpatternandantifungalsusceptibilityofepisodesof
candidemiadocumentedinonly11outof21LatinAmericancountriesand1outof20Caribbean
countriesandterritories. Takingtogetheralldataavailable,wewereabletocharacterizethespecies
J.Fungi2017,3,24 3of14
distributioninmorethan12,000episodesofCandidabloodstreaminfectionsdocumentedin40medical
centersfromourregion(Table1,Figure1,andSupplementaryMaterials). AmongallCandidaspp.
isolatesanalysedforspeciesdistribution,only5460isolateshadtheirantifungalsusceptibilityprofile
performedin17studies(Table2).
Table1. SpeciesdistributionofCandidabloodstreamisolatesfromLatinAmericanandCaribbean
medicalcenters(1997–2016).
ne SpeciesDistribution(%)
Country/Territory Reference Period
(No.ofCenters) Caa Cpa Cta Cglaa Cka C.guia OCSb
Argentina Roderoetal.(2005)[28]c 1999–2000 253(36) 42.5 29.9 16.5 2.7 1.18 0.39 6.83
Argentina Cordobaetal.(2011)[29]c 2007–2008 420(47) 42.1 28.5 16.9 4.7 0.47 1.66 5.67
Argentina LopezMoraletal.(2012)[30]c 2005–2008 683(16) 41.3 24.3 19.9 6.3 0.59 1.76 5.85
Argentina Rieraetal.(2014)[31] 2010–2012 158(4) 41 20 12 10 1.5 3 12.5
Brazil Colomboetal.(1999)[32] 1995–1996 145(6) 37 25 24 4 1 2 7
Brazil Costaetal.(2000)[33]c 1994–1996 84(1) 51.2 17.8 11.9 2.3 1.19 9.5 6.11
Brazil Colomboetal.(2003)[34] 1996–1998 200(5) 41.5 20.5 24 4.5 1 2 6.5
Brazil GoldaniandMario(2003)[35]c 1996–1999 101(1) 32.6 23.7 26.7 8.9 1.9 0 6.2
Brazil Antunesetal.(2004)[36] 2002–2003 120(1) 48.3 25.8 13.3 3.3 1.7 1.6 6
Brazil Aquinoetal.(2005)[37] 1998–2004 131(1) 45 24.4 15.3 6.9 4.6 0.76 3.04
Brazil Colomboetal.(2006)[38] 2003–2004 712(11) 40.9 20.5 20.9 4.9 1.1 2.4 9.3
Brazil Medranoetal.(2006)[39] 2000–2002 50(1) 28 36 16 4 0 12 4
Brazil Colomboetal.(2007)[40] 2002–2003 282(4) 38 23 17 3 1 6 12
Brazil daMattaetal.(2007)[41] 1995–2003 1000(4) 40 23.8 24.3 4.4 0.6 3 3.9
Brazil Giraoetal.(2008)[42] 1999–2006 108(1) 40 18 34 1 3 1 3
Brazil Francaetal.(2008)[43] 2001–2004 100(1) 59 9 15 7 2 2 6
Brazil Mottaetal.(2010)[44] 2006 136(1) 52.2 22.1 14.7 6.6 1.6 0.8 2
Brazil SampaioCamargoetal.2010[45] 1997–2007 151(1) 44 22 15 9 6 0.66 3.34
Brazil Bonfiettietal.(2012)[46] 1998–2006 100(1) 44 37 13 5 1 0 0
Brazil Hoffmann-Santosetal.(2013)[47] 2006–2011 130(2) 34.6 38.4 18.4 5.3 0 1.5 1.8
Brazil Morettietal.(2013)[48] 2006–2010 313(1) 44 14.4 21.7 11.2 3.5 1.3 3.9
Brazil Colomboetal.(2013)[15] 2006–2007 300(9) 34 26 24 7 3 2 4
Brazil Santosetal.(2014)[49] 1995–2009 422(1) 35.7 46.6 9.7 3.5 0.94 1.65 1.91
Brazil Colomboetal.(2014)[2] 2003–2012 1392(22) 42 19 20 9 1.14 0.86 8
Brazil daCostaetal.(2014)[50] 2006–2011 108(1) 28.7 24.1 30.5 8.3 1.8 0 6.6
Brazil Doietal.(2016)[51] 2007–2010 137(16) 34.3 24.1 15.3 10.2 1.5 0.7 13.9
Colombia Cortesetal.(2011)[52]c 2001–2007 1622(27) 50.9 15.5 15.5 2 2.36 3.3 10.44
Colombia Cortesetal.(2013)[53] 2004–2008 382(7) 56 16 17.3 2.6 0.8 0 7.3
Colombia Cortesetal.(2014)[54] 2008–2009 131(7) 66.4 14.5 10.6 1.5 0 1.5 5.5
Colombia OrtizRuizetal.(2016)[55] 2008–2012 81(3) 52 17 17 6 3 4 1
CostaRica Villalobosetal.(2016)[56] 2007–2011 210(1) 38 42 10 7 NRf NR 3
Mexico Gonzalezetal.(2008)[57] 2004–2007 398(5) 31.9 37.9 14.8 8 2.7 1.3 3.3
Mexico Corzo-Leonetal.(2014)[58] 2008–2010 74(2) 46 5 26 13.5 5 3 1.5
Peru Bustamanteetal.(2014)[59] 2009–2011 153(1) 39.9 28.1 23.5 5.2 0.7 2 0.6
PuertoRico Conde-Rosaetal.(2010)[60] 2005–2006 85(1) 28 49 17 4 1 0 1
Venezuela Francoetal.(2008)[61] 2003–2005 154(6) 18.8 26 39 7.8 2.6 0 5.8
Multicd Pfalleretal.(2000)[62] 1997–1998 107(7) 43 26.1 16.8 6.6 0.9 0 6.6
Multic Pfalleretal.(2001)[63] 1997–1999 132(9) 45 25 16 6 1 NR 7
Multic Godoyetal.(2003)[64] 1999–2000 103(5) 42 21.3 24.2 7.7 0 2.9 1.9
Multic Nuccietal.(2013)[7] 2008–2010 672(21) 37.6 26.5 17.6 6.3 2.7 6.5 2.8
aCa:C.albicans.Cp:C.parapsilosis(sensulato).Ct:C.tropicalis.Cgla:C.glabrata.Ck:C.krusei.Cgui:C.guilliermondii
(sensulato); b OtherCandidaSpecies—speciesotherthanC.albicans. C.parapsilosis(sensulato). C.tropicalis.
C.glabrata.C.krusei.C.guilliermondii(sensulato);cFungemiacollection.Percentageofspeciesdistributionwas
recalculatedtakinginaccountonlyCandidaspeciesasdenominator;dMulticenterstudiesincludingdifferent
countriesinLatinAmerica;eNumberofCandidaisolates;andfNR:NotReported.
C.albicans,C.parapsilosis(sensulato),C.tropicalis,andC.glabratawerethemostcommonlyfound
speciescausingcandidemiainallcountries. C.albicanswasthemaincauseofcandidemiain32outof
40studiesexhibitingprevalenceratesrangingbetween18.8%and66%. Thehighestprevalencerateof
C.albicanscandidemiawasreportedbyCortesetal. (2014)inColombia[54]. Itisworthtomention
thatall4studiesfromColombiahadC.albicansprevalencerateshigherthan50%. Incontrast,less
than30%ofprevalenceratesofC.albicansstrainswerereportedinBrazilbyMedranoetal. (2006)and
daCostaetal. (2014),byConde-Rosaetal. (2010)inasinglestudyreportedinPuertoRico,andby
Francoetal.(2008)inVenezuela[39,50,60,61]. Inthesestudies,C.tropicalisand/orC.parapsilosiswere
themostcommonlyfoundspeciescausingcandidemia.
C.parapsilosis(sensulato)isolatesrangedfrom5%to49%ofallcandidemicepisodes. Indeed,
C.parapsilosiswasidentifiedasthemainagentofCNAspeciescandidemiain25outof40studies,and
in6ofthestudiesitsurpassedtheprevalencerateofC.albicans.
J.Fungi2017,3,24 4of14
Table2.AzoleresistanceratesofC.albicans,C.parapsilosis(sensulato)andC.tropicalisbloodstream
isolatesfromLatinAmericanmedicalcenters(1997–2016).
Fluconazole Voriconazole
Country Reference;NumberofIsolates Method Species
SDDa Rb SDD R
Roderoetal.(2006)[28]; CLSIc× Cae NRi 15.7%(1.8%) NTj NT
Argentina n=265 (EUCAST) Cpf NR 0%(0%) NT NT
Ctg NR 43%(5.4%) NT NT
Cordobaetal.(2011)[29]; EUCASTd Ca NR 0% NR 0.5%
Argentina n=420 Cp NR 2.5% NR 0.8%
Ct NR 4.2% NR 4.2%
Colomboetal.(2003)[34]; CLSI Ca 1.2% 0% NT NT
Brazil n=200 Cp 0% 0% NT NT
Ct 0% 0% NT NT
Antunesetal.(2004)[36]; CLSI Ca 0% 0% NT NT
Brazil n=120 Cp 0% 0% NT NT
Ct 0% 0% NT NT
Aquinoetal.(2005)[37]; CLSI Ca 0% 0% NT NT
Brazil n=131 Cp 0% 0% NT NT
Ct 0% 0% NT NT
Colomboetal.(2006)[38]; CLSI Ca 0.3% 0.3% 0% 0.3%
Brazil n=712 Cp 0% 0% 0% 0%
Ct 1.3% 0% 0% 0%
Colomboetal.(2007)[40]; CLSI Ca 0% 0% NT NT
Brazil n=282 Cp 0% 0% NT NT
Ct 0% 0% NT NT
daMattaetal.(2007)[41]; CLSI Ca 0% 0% 0% 0%
Brazil n=1000 Cp 0% 0% 0% 0%
Ct 0% 0% 0% 0%
Bonfiettietal.(2012)[46]; EUCAST Ca 0% 0% 0% 0%
Brazil n=100 Cp 6% 0% 0% 3%
Ct 0% 0% 0% 0%
Colomboetal.(2013)[15]; CLSI Ca 0% 0% 0% 0%
Brazil n=300 Cp 1.3% 0% 0% 0%
Ct 2.5% 0% 0% 0%
Santosetal.(2014)[49]; CLSI Ca 9.9% 0% 2.6% 0%
Brazil n=422 Cp 7% 0% 3.5% 0%
Ct 19.5% 7.3% 12% 4.9%
daCostaetal.(2014)[50]; EUCAST Ca NR 3.7% NR 3.7%
Brazil n=108 Cp NR 26.9% NR 0%
Ct NR 3,2% NR 3.2%
Gonzalezetal.(2014)[57]; CLSI Ca 0% 0.8% 0% 0.8
Mexico n=398 Cp 0% 0% 0% 0%
Ct 0% 0% 0% 0%
Corzo-Leonetal.(2014)[58]; CLSI Ca 0% 0% 0% 0%
Mexico n=74 Cp 0% 0% 0% 0%
Ct 0% 0% 0% 0%
Bustamanteetal.(2014)[59]; CLSI Ca NR NR 0% 5%
Peru n=153 Cp NR 2.3% NR NR
Ct NR NR NR NR
Multicenter Godoyetal.(2003)[64]; CLSI Ca 0% 0% NT NT
studiesh n=103 Cp 0% 0% NT NT
Ct 0% 0% NT NT
Multicenter Nuccietal.(2013)[7]; CLSI Ca 0,4% 0% 0% 0%
studies n=672 Cp 1,1% 0% 0% 0%
Ct 0% 0% 0% 0%
aSusceptibleinadose-dependentmanner;bResistanttoazoles;cClinicalLaboratoryStandardInstitute;dEuropean
Committee on Antimicrobial Susceptibility Testing; e C. albicans; f C. parapsilosis (sensu lato); g C. tropicalis;
hMulticenterstudiesincludingdifferentcountriesfromLatinAmerica;iNR:Notreported;jNT:Nottested.
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J. Fungi 2017, 3, 24 4 of 13

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ALmateinri cAamnearnidcaCn aarnibdb Ceaanribmbeedainc amlceednictaerl sce(1n9te9r7s– 2(1091967).–2a0O16th).e ar OCtahnedr iCdaanSdpiedcaie Ssp—ecspieesc—iesspoetchieesr tohthaner
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blaCt.og);u ibl lCie.r mguonildliieir(mseonndsuii l(asteon)s;uc Cla.tpoa)r; acp sCil.o spiasr(aspesnilsousisla (tsoe);ndsuM luatltoi)c;e nd tMeruslttuicdeinetseirn cstluuddiiensg idnicffluerdeinntg
cdoiuffnetrreienst fcrooumntLriaetsin frAomm eLraictain. America.
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ratesirsaonlagteins gfrobmet Lwaetienn A9m.7e%ricaann mde3d9ic%al. cOenftenros t(e1,99C7.–2t0ro1p6i)c. alis was the main cause of CNA species
candidemia in 1R3eofeuretnocef; 4N0umstbuedr oief s. Franco et al. (2008) and da CosFtluacoentaazlo.le( 2014) repVoorritceodnaztholaet
Country Method Species
C.tropicalissurpassedCIs.olaaltbeisc ansintheirsurveysofcandidemia[5S0D,6D1]a. In2casRu bi sticscoSnDdDu ctedRby
Cortesetal. (20R1o1d)earon edt aOl. r(2ti0z06R) [u2i8z]; etal. (2C0L1S6I )c, ×C .parapCsail eo s is(senNsRu i lato)1a5n.7d% C(1..8t%ro) picaNlisT ij nfecNteTd
Argentina n = 265 (EUCAST) Cp f NR 0% (0%) NT NT
exactlythesamepercentageofpatients[52,55].
Ct g NR 43% (5.4%) NT NT
PrevalenceratesofC.glabratapresentedalargevariationamongstudiesdocumentedindifferent
Cordoba et al. (2011) [29]; EUCAST d Ca NR 0% NR 0.5%
coAurngterniteins.a In generaln, =C 4.20g labrata represent ed the thirCdp or fourNthR most co2m.5%m on CNNAR spe0c.i8e%s
documentedinCandidablo odstreaminfections ,exhibitingCpt revalencNeRr atesrang4i.n2%g from1%NRt o134.5.2%% .
Colombo et al. (2003) [34]; CLSI Ca 1.2% 0% NT NT
ThehighestrateforthisspecieswasfoundbyCorzo-Leonetal. (2014)inMexicowhereC.glabratawas
Brazil n = 200 Cp 0% 0% NT NT
consideredthesecondmostcommoncauseofCNAcandidemiabehindonlyC.tropicalis[58].
Ct 0% 0% NT NT
PrevalenceArnatutenseso eft aCl. .(2k0r0u4s) e[3i6s]t; rains ranCLgSeId from 0Ctoa 6% amo0%n g all stud0i%es . C. guiNllTie rmonNdTi i
(sensBurazlailt o)wasisolatedn =i n12303 out40studies,be ingreporteCdp inalmos0t%a llcountri0e%s represenNtTe dintNhTis
Ct 0% 0% NT NT
review. TheprevalenceofC.guilliemondiicandidemiarangedfrom0to12%. Thehighestprevalence
Aquino et al. (2005) [37]; CLSI Ca 0% 0% NT NT
rateofC.guilliermondiicandidemiawasfoundinHonduras,asreportedbyNuccietal. (2013),along
Brazil n = 131 Cp 0% 0% NT NT
withthecharacterizationo f672episodesofcan didemiacaCrt riedout0i%n LatinAm0e%ri ca[7]. NT NT
All speciesCooltohmebro teht aaln. (2C0.06a)l b[3i8c]a; ns, C. paCrLaSpIs ilosis (senCsa u lato),0C.3.%t ropicalis,0.C3%. glabrata0,%C . kru0.s3e%i,
andBCra.zgilu illiermondii(sne n= s7u12 lato)were classifi ed asotherCpC andidas0p%e cies(OCS0%s) . Thehi0g%h estr0a%te
Ct 1.3% 0% 0% 0%
of OCSs among the studies retrieved was observed by Doi et al. (2016) in Brazil with 13.9% of its
Colombo et al. (2007) [40]; CLSI Ca 0% 0% NT NT
collection[51]. Overall,themostcommonspeciesdocumented,inatleast5outof40studies,were
Brazil n = 282 Cp 0% 0% NT NT
C. rugosa, C. pelliculosa, C . lusitaniae, C. famata , C. lipolytiCcta , and C.0%ke fyr. The O0%C Ss lessNfrTe quenNtTly
isolated were Cd.a hMaaetmtau elto anl.i (i2,0C07.) i[n41te];r media, CC.LSsIa ke, C. holCma ii, C. zey0l%a noides, C.0u%t ilis, C. v0i%sw anat0h%ii ,
Brazil n = 1000 Cp 0% 0% 0% 0%
C.dubliniensis,andC.novergensis.
Ct 0% 0% 0% 0%
Overall,wewereabletoidentifyhistoricaltrendsinspeciesdistributionofCandidaspp. only
Bonfietti et al. (2012) [46]; EUCAST Ca 0% 0% 0% 0%
relatBerdaztilo prevalenceonf =C 1.0g0l abrata. Inthisreg ard,asilluCstpr atedon6T%a ble1,onl0y%1 outof80%B razil3ia%n
studiespublishedbetween 1997and2006pres entedprevCatl encerate0s%o fC.glabr0a%ta candid0e%m ia≥07%% .
Otherwise, 7 ouCotloomfb1o4 est taul. d(2i0e1s3)p [1u5b];l ished bCetLwSIe en 2007Caan d 20160e%x hibited pr0e%v alence r0a%t es ≥07%% .
Brazil n = 300 Cp 1.3% 0% 0% 0%
Similarly,inArgentinatherewasasubstantiallyincrementofC.glabrataratesmovingfromarateof
Ct 2.5% 0% 0% 0%
Santos et al. (2014) [49]; CLSI Ca 9.9% 0% 2.6% 0%
Brazil
n = 422 Cp 7% 0% 3.5% 0%
J.Fungi2017,3,24 6of14
2.7%inthefirststudyreportedin2005to10%inarecentcasuisticinvolving158episodesofcandidemia
reportedbyRieraetal. (2014)[31]. InColombia,prevalenceratesofC.glabrataincandidemiaremained
lowerthan3%alongthefirst3studies,asillustratedonFigure1,movingupto6%inarecentstudy
involving81episodesoffungemia.
ItisseemsthattherewasaslightincreaseintheprevalencerateofC.kruseicandidemiainBrazil.
Indeed,7outof8studiesfromBrazilexhibitedprevalenceratesofC.krusei≤2%between1997and
2006[32,33,35,36,38,39,64]. Incontrast,5outof14studiespublishedbetween2007and2016exhibited
isolationrates≥2%forthisparticularspecies[15,42,43,45,48]. PrevalenceratesofC.kruseicandidemia
remainedstablealongdifferentstudiesreportedinArgentinaandColombia(seeTable1).
TemporalTrendsofAntifungalResistancetoAzolesandEchinocandins
Anoverallreviewofthe40studiesretrievedforCandidaspeciesdistributionanalysis,only17
of them presented reliable information on the antifungal susceptibility tests of strains using broth
microdilution methods standardized by CLSI and EUCAST. In order to check for trends in terms
ofrisingantifungalresistancealongthestudyperiod,wecompareddatafrom7studiespublished
between1997and2006todatageneratedfrom10studiespublishedbetween2007and2016(Table2).
Ten out of the 17 studies providing data on Candida antifungal resistance were performed in
Brazilian medical centers, 2 were from Argentina, 2 from Mexico, and 1 from Peru. We included
ananalysisofdatageneratedbytwomulticenterstudiesthatprovidedadditionalinformationfrom
Argentina,Brazil,Chile,Colombia,Ecuador,Honduras,Peru,andVenezuela.
Reviewingtheantifungaldrugsthatwereevaluatedalongthe17studies,wefoundthatonly
fluconazolewastestedinallthem,followedbyamphotericinBin15studies. Otherdrugsfrequently
testedincludedvoriconazole(11studies),caspofungin(5studies),andanidulafungin(4studies). Data
onmicafunginwasonlyreportedinonestudy.
It is important to mention that no single author from the Latin American surveys reporting
rates of antifungal resistance of Candida bloodstream isolates, either to triazoles or echinocandins,
attemptedtoconfirmtheirinvitroprofilebycheckingtheexpressionofmolecularmechanismsof
antifungalresistance.
(i) Trends in resistance to fluconazole and voriconazole among C. albicans, C. tropicalis, and
C.parapsilosisisolates.
Resistance to azoles among isolates of C. albicans, C. tropicalis, and C. parapsilosis remained
relatively unchanged over time. Except for one single study conducted by Rodero et al. (2005)
in Argentina, all studies carried out prior to 2006 showed that less than 1% of isolates exhibited a
non-susceptible(susceptibleinadosedependentmanner[SDD]orresistant)phenotypetofluconazole
andvoriconazole. RegardingtheArgentineancasuistic,theauthorsreportedfluconazoleresistance
ratesof15.7%and1.8%forC.albicans,and43%and5.4%forC.tropicalis,byusingCLSIandEUCAST,
respectively[28].
After2007,aslightincreaseinthepercentageofresistancetofluconazolewasnoted. Overall,
resistanceratestofluconazoleincreasedfrom0.4%to1.2%amongC.albicans,from0.5%to2.3%among
isolatesofC.tropicalis,andfrom0to2.6%forC.parapsilosis[7,15,29,46,49,50,57,59]. Forvoriconazole,
resistanceratesremainedaround1%.
(ii) TrendsinresistancetoechinocandinsamongCandidaspp.
Only7outof17studies,allpublishedafter2007,haveprovideddataonantifungalsusceptibility
ofatleastoneofthe3echinocandinsavailableforclinicaluseinLatinAmerica. Ofnote,echinocandin
resistancewasreportedinonly3outof7mentionedstudies. InBrazil,Santosetal. (2014)reported
that3outof15(20%)ofC.glabrataisolateswerenon-susceptibletocaspofungin[49]. Similardatawere
observedbyBustamanteetal. (2014)inPeruwhere1outof8(12.5%)ofC.glabratastrainswasresistant
toanidulanfungin[59]. Theonlystudyreportinginvitroechinocandinresistanceagainstspeciesother
J.Fungi2017,3,24 7of14
than C. glabrata was conducted by Cordoba et al. (2011) in Argentina where they found 26 out of
120(21.6%)ofC.parapsilosisisolatesresistanttoanidulafunginbyusingtheEUCASTmicrodilution
method[29].
4. Discussion
Candidemiaremainsasignificantpublichealthproblemworldwide[1–7]. InLatinAmerica,the
incidence rates range from 0.74 to 6.0 per 1000 hospital admissions [30,38,45,48,56,58]. Despite all
advancesrelatedtothedevelopmentofnewdiagnosticandtherapeutictoolsforfungalinfections,
crudemortalityratesofcandidemiaremainhighinLatinAmericanmedicalcenters,rangingfrom30
to76%[28,42,44,51,55,56,58,60].
Asexpected, C.albicansremainsthemostcommonspeciescausingcandidemiainourregion,
followed by C. parapsilosis and C. tropicalis [65,66]. Otherwise, prevalence rates of C. glabrata were
highlyvariablewithindifferentstudiesanddifferentcountries. Thesamevariationobservedamong
severalcountrieswasnotedinonerecentglobaltrendreviewofCandidaspeciesdistribution,where
prevalenceratesofC.glabrataincandidemicpatientsinEuropeanmedicalcentersrangedbetween
8%(Spain)and20%(Denmark)[10]. InBrazil,ArgentinaandColombia,wenotedatrendtowardsan
increaseinC.glabratafrequency[28,31,41,48]alongtheperiodofstudy. Thisincreasehasanimportant
clinicalimpact,asC.glabratashowsadiminishedsusceptibilitytoazolesand,eventually,candins[27].
Althoughtheexplanationforthisshiftisnotcompletelyunderstood,itseemstobeaconsequenceof
theincreasedexposuretofluconazole,aspreviouslydemonstratedbyseveralauthors[5,13].
C.kruseiandC.guilliermondii(sensulato)frequencieshavenotdemonstratedsubstantialchanges
in their frequency, but both species were found in most studies from different countries. In fact,
C.kruseiwasfoundin36outof40articles,whileC.guilliermondii(sensulato)wasfoundin33. Ofnote,
in the single multicenter study conducted by Nucci et al. (2013) in 7 countries, C. guilliermondii
rangedfrom1.6%to20%[7]. Duetotheirreducedsusceptibilitytofluconazole,bothC.kruseiand
C.guilliermondiimayhavearelevantclinicalimpactintermsofdefiningstrategyforempiricaltherapy
ofriskpatients[67,68].
One limitation found in all studies reviewed is that only phenotypic methods were used to
identifyCandidaspeciesinvolvedintheepisodesofcandidemia. Consequently,accurateidentification
ofcrypticspeciesofCandidacouldnotbeprovided.Inaddition,wemaynotexcludethepossibilitythat
theOCSsreportedbytheauthors,includingC.rugosa,C.pelliculosa,C.lusitaniae,C.famata,C.lipolytica,
andC.kefyr,weremisidentifiedbyinaccuratephenotypicmethodsusedbytheroutinelaboratories.
ThereisaconsensusthatMALDI-TOFandsequencingoftheInternalTranscribedSpacer(ITS)region
ofribosomalDNAarebothconsideredtobefarmoreaccurateandreliableforprovidingidentification
ofcrypticandrarespeciesofCandidathanconventionalmethods[69–71].
Inthisregard,despitethefactthatC.aurisstrainshavenotbeendetectedasOCSscausinginfection
alongthe40mentionedsurveysofcandidemiaperformedinourregion,tworecentreportsdocumented
outbreaks of C. auris candidemia in medical centers from Venezuela and Colombia [72,73]. This
microorganismhasbeenrecognizedasamultidrug-resistantyeastpathogensinceallC.aurisstrainsare
fullyresistanttofluconazoleandpartofthemmaybeeitherresistanttocandinsand/oramphotericin
B.Wemaynotexcludethepossibilitythattherealprevalenceofthisemergingmultidrug-resistant
yeastpathogenisunderestimatedinourregionsinceithasbeenmisidentifiedinroutinelaboratories
asC.famataandC.haemulonii,amongothers[74].
Fluconazole resistance has been increasingly noted in Candida spp., not only with C. glabrata
butalsoamongstrainsinitiallydescribedasprimarilysensitivetoazolessuchasC.parapsilosisand
C.tropicalis[8,10,20–22,24,75–77]. Inthereviewpresented,wedecidednottofocusouranalysison
fluconazoleresistanceagainstC.glabratastrainssincefluconazoleisnotconsideredasafealternative
anymorefortreatingcandidemicpatientsinfectedbythispathogen[67,68].
SeveralstudieshavereportedvariationsinfluconazoleresistanceratesamongC.parapsilosisand
C.tropicalisisolates. Indeed,resistanceratesamongC.parapsilosisisolatesrangedfrom3.4%to7.5%in
J.Fungi2017,3,24 8of14
USAandfrom0to6%inEurope[8,20–22,75–78]. ForC.tropicalis,resistanceratesrangedfrom2.4%
to11.6%inUSAandfrom1.7%to22%inEurope[8,20–22,75–78]. InLatinAmerica,wehavenoted
a slight increase in C. albicans, C. parapsilosis, and C. tropicalis isolates exhibiting a non-susceptible
profiletofluconazolealongourstudyperiod. Indeed,resistanceratestofluconazoleincreasedfrom
0.4%to1.2%amongC.albicansisolates; from0.5%to2.3%amongisolatesofC.tropicalisandfrom
0to2.6%forC.parapsilosisstrains. Ofnote,thoughstillconsideredrare,arecentpublicationfrom
BrazildescribedanoutbreakofC.parapsilosis(sensustricto)candidemiainvolving23intensivecare
unit(ICU)patientsfromasingleinstitution[24]. ResistancetofluconazoleinC.parapsilosisstrainsin
thisparticularreportwasconfirmedbythepresenceofERG11mutationsandoverexpressionofefflux
pumpsbythementionedstrains[79].
ResistancetoechinocandinshasbeendescribedasanuncommonphenomenonamongC.albicans,
C. parapsilosis, C. tropicalis, and C. krusei isolates [80]. However, it has become increasingly
commonamongC.glabratastrainsfrompatientsadmittedinUSandEuropeanhospitals[27,80–82].
InLatinAmerica,apparently,echinocandinresistanceremainsrare. Itisimportanttomentionthat
echinocandinsarerarelyusedforthetreatmentofcandidemicpatientsinLatinAmericainspiteofthe
drug’savailabilityintheearly2000s.
AccordingtoNuccietal. (2013),only40(5.9%)outof672patientswithcandidemiadocumented
between2008and2010wereinitiallytreatedwithechinocandins[7]. Anotheraspecttoconsideristhat
antifungalresistanceinLatinAmericamaybeunderestimatedsincemostroutinelaboratoriesdonot
performantifungalsusceptibilitytests.
Inouranalysis,only3outof40studiesdocumentedanyrateofechinocandinresistancewith
Candidasp. bloodstreamisolates. Santosetal. (2014)andBustamanteetal. (2014)reportedresistance
ratesof20%and12.5%toechinocandinsamongC.glabrataisolates,respectively[49,59]. Cordobaetal.
(2011)reportedthat21.6%ofC.parapsilosisisolateswereresistanttoanidulafungin[29]. However,the
highratesofresistancereportedbythesepapersshouldbeinterpretedverycarefullysincetheyhave
notconfirmedtheechinocandinresistancephenotypebycheckingthepresenceoffksmutationsinall
isolatesexhibitinghighvaluesofminimuminhibitoryconcentration(MIC)forechinocandins.
Currently, only two reports from medical centers in Latin America have demonstrated
microbiological and molecular echinocandin resistance against Candida bloodstream isolates.
Bizerraetal. (2014), using sequencing methodology for the study of FKS genes and quantification
ofglucansynthesis,reportedtheoccurrenceofamutationassociatedwiththeresistancephenotype
againstechinocandinsinC.glabrataisolatedfromasinglecancerpatientwithcandidemiaexposed
to antifungal prophylaxis with micafungin [25]. Finally, Forastiero et al. (2015) reported a rapid
developmentofresistanceinC.kruseiisolatesrecoveredfromapatientundercaspofungintreatment.
ClinicalresistancewasassociatedwithincreasedechinocandinMICsandwasultimatelyrelatedto
newmutationsofthetargetenzyme(fks1)[83].
5. Conclusions
Inconclusion,therehasbeenachangingepidemiologyofCandidabloodstreaminfectionover
thepastyearsinLatinAmerica. AlthoughC.albicansremainsthepredominantcauseofcandidemia,
a shift has been reported in the epidemiology as some CNA species have emerged as the cause
ofcandidemia, andtheycanexhibitresistancetofluconazoleandechinocandins. Severalmedical
centershavereportedepisodesofcandidemiaduetoC.tropicalisandC.parapsilosisisolatesresistant
tofluconazole. Echinocandinresistanceconfirmedbymolecularstudieshasbeenreportedinonly
two episodes of candidemia reported in patients assisted at medical centers from Latin America,
andappearstoberareinourregion. Continuousmulticentersurveillancestudiesofcandidemiain
LatinAmericaarenecessarytodetectanyregionalandhistoricaltrends,intermsofCandidaspecies
distributionandemergenceofantifungalresistance,early. Thisinformationiscriticaltocliniciansin
preventingandcontrollingCandidabloodstreaminfectionsinourmedicalcenters.
J.Fungi2017,3,24 9of14
SupplementaryMaterials:Thefollowingareavailableonlineatwww.mdpi.com/2309-608X/3/2/24/s1.
Acknowledgments:WethankMaryNagel,QMSconsultant(USA)fromLaboratoireNacionaldeSantéPublique
inHaiti,forreviewingthismanuscript.DanielArchimedesdaMattaandAnaCarolinaRemondiSouzareceiveda
post-docscholarshipfromComissãodeAperfeiçoamentodePessoaldoNívelSuperior(CAPES)inthePrograma
NacionaldePósDoutorado(PNPDProgram),Brazil.ArnaldoLopesColomboreceivedgrantsfromConselho
NacionaldeDesenvolvimentoCientíficoeTecnológico,Brazil,(CNPq,Grant307510/2015-8).
Author Contributions: Daniel Archimedes da Matta reviewed the literature, retrieved the articles and was
responsibletoanalyseandwriteaboutCandidaspeciesdistribution. AnaCarolinaRemondiSouzawrotethe
topicantifungalresistanceandformattedthemanuscriptaccordingtoJournalofFungi.ArnaldoLopesColombo
designedthestudystrategy,wrotepartofthediscussionandreviewedthewholemanuscript.
ConflictsofInterest:ArnaldoLopesColombohasreceivededucationalgrantsfromAstellas,Gilead,Pfizer,and
UnitedMedicalandresearchgrantsfromAstellasandPfizer.Allotherauthors:nonetodeclare.
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