Nosocomial Candidiasis: Antifungal Stewardship and the Importance of Rapid Diagnosis

22 Pages·2015·0.59 MB·English

MedicalMycology,2016,54,1–22
doi:10.1093/mmy/myv076
AdvanceAccessPublicationDate:18September2015
ReviewArticle
Review Article
Nosocomial Candidiasis: Antifungal
Stewardship and the Importance of Rapid
Diagnosis D
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Michael A. Pfaller1,2,3,4,∗ and Mariana Castanheira2 loa
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1T2Biosystems,Lexington,Massachusetts,2JMILaboratories,NorthLiberty,Iowa,3UniversityofIowa fro
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CollegeofMedicineand4CollegeofPublicHealth,IowaCity,Iowa h
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*Towhomcorrespondenceshouldbeaddressed:MichaelA.Pfaller,MD,345BeaverKreekCentre,SuiteA,NorthLiberty, ://a
Iowa52317.Tel:+[phone];Fax:+[phone];E-mail:[email protected] c
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e
Received18March2015;Revised8July2015;Accepted20July2015 m
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Abstract p
.c
o
m
Candidemia and other forms of candidiasis are associated with considerable excess /m
mortalityandcosts.Despitetheadditionofseveralnewantifungalagentswithimproved m
y
spectrumandpotency,thefrequencyofCandidainfectionandassociatedmortalityhave /artic
not decreased in the past two decades. The lack of rapid and sensitive diagnostic tests le
-a
hasledtoconsiderable overuse ofantifungalagentsresultinginincreased costs,selec- b
s
tion pressure for resistance, unnecessary drug toxicity, and adverse drug interactions. tra
c
Both the lack of timely diagnostic tests and emergence of antifungal resistance pose t/5
4
considerableproblemsforantifungalstewardship.Whereasantifungalstewardshipwith /1/1
afocusonnosocomialcandidiasisshouldbeabletoimprovetheadministrationofanti- /25
7
fungaltherapyintermsofdrugselection,properdoseandduration,sourcecontroland 94
7
de-escalationtherapy,animportantparameter,timelinessofantifungaltherapy,remains 4 b
y
avictimofslowandinsensitivediagnostictests.Fortunately,newproteomicandmolecu- g
u
lardiagnostictoolsareimprovingthetimetospeciesidentificationanddetection.Inthis es
reviewwewilldescribethepotentialimpactthatrapiddiagnostictestingandantifungal t on
0
stewardshipcanhaveonthemanagementofnosocomialcandidiasis. 3
A
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Keywords:Candida,antifungalstewardship,rapiddiagnostictest,resistance. ril 2
0
1
9
Introduction theintroductionofseveralextended-spectrumtriazoleand
echinocandinantifungalagentsforuseinprophylaxis,em-
Nosocomial candidiasis (candidemia and other forms of
piricandtargetedtherapy[1,3–8].Whereasthehighmor-
invasivecandidiasis[IC;infectioninvolvingothernormally
talityrateisinpartrelatedtothecriticallyillpatientpopu-
sterilebodyfluidsandtissues])constitutesalife-threatening
lationatriskforICwhoaresubjectedtobothinvasiveand
conditioninimmunocompromisedandcriticallyillpatients
immunosuppressive modalities, it may also be attributed
[1,2].Althoughthisiswidelyacknowledged,itisalsoclear
to the difficulty in diagnosing Candida infection coupled
that the frequency of infection and the associated mortal-
withchallengesinadministeringadequateantifungalther-
ity has not decreased over the past two decades despite
apy(timelyadministration,rightdrug,rightdose,sufficient
(cid:2)CTheAuthor2015.PublishedbyOxfordUniversityPressonbehalfofTheInternationalSocietyforHumanandAnimalMycology. 1
Allrightsreserved.Forpermissions,pleasee-mail:[email protected]
2 MedicalMycology,2016,Vol.54,No.1
duration) to those patients who need it [9–17]. Although tionswillrequireamuchmorerapid,sensitive,andspecific
thismaysuggestaroleforempiricorpresumptivetherapyin approachtodiagnosisaswellasincreasedattentiontothe
themanagementofcandidiasis[10,18,19],criteriaforini- time-sensitiveaspectsofadministrationofantifungalther-
tiating such therapy remain poorly defined and frequently apy[24,55–62].
lead to widespread administration of antifungal therapy
withtheattendantrisksoftoxicity,resistanceselectionand
Principlesofantifungalstewardship
unnecessarily high costs of antifungal treatment regimens
[10,18,20–22].Theseissuesarecompoundedbythelackof Thebasicprinciplesofantifungalstewardshipwithafocus
rapid,sensitiveandspecificdiagnostictests[9,23].Clearly, onICaresharedwiththealreadyestablishedantibacterial
antifungal stewardship should be able to make consider- stewardship programs [52,63]. The major purpose of all
ableimprovementsintheprocessofdiagnosingandtreat- stewardship efforts is to optimize the use of antimicrobial
ingIC[24].Inthisreviewwewilldiscussthepotentialrole agents to achieve the best outcomes while minimizing ad-
D
ofantifungalstewardshipandhowrapiddiagnosticmeth- verse events and limiting the selection pressures that drive o
w
n
ods can impact stewardship efforts in the management of the emergence of resistance [52,60,63–65]. Guidelines for lo
a
candidiasis. the development of an effective antimicrobial stewardship de
d
program have been published by the Infectious Diseases fro
Society of America (IDSA) and the Society for Healthcare m
Burdenofdisease EpidemiologyofAmerica(SHEA)[63]andadaptedtothe http
s
Candidiasis is the most important fungal infection in needs of antifungal stewardship by Ananda-Rajah et al. ://a
c
hospitalized individuals worldwide [1,2,8,18,25]. A US [24].KeyrecommendationsfromtheseGuidelinesinclude, a
d
e
population-basedsurveyconductedbytheCentersforDis- butarenotlimitedto,thefollowing:(i)Thecompositionof m
ic
ease Control and Prevention (CDC) during 2008–2011 the stewardship team must be multidisciplinary and opti- .o
u
foundameanannualincidenceofcandidemiaper100,000 mallyshouldincludeaninfectiousdiseases(ID)physician, p.c
o
population of 13.3 in Atlanta and 26.2 in Baltimore [5]. aclinicalpharmacistwithIDtraining,aclinicalmicrobiol- m
Rateswerehighestamongadultsaged≥65years(Atlanta, ogist,aninformationsystemspecialist,aninfectioncontrol /mm
y
59.1;Baltimore,72.4).SimilarfindingswerenotedinDen- professional and a hospital epidemiologist. Collaboration /a
mark[3]wheretheannualincidencewas8.6/100,000pop- between these individuals and with the Infection Control rtic
le
ulation with the highest rates seen at the extremes of age andPharmacyandTherapeuticscommitteesisessentialand -a
b
(<1yr[11.3/100,000]and>70yrs[37.1/100,000]).These mustbesupportedbyhospitaladministrationandmedical stra
c
elevatedcandidemiaratesareincontrastwiththoseofother staff leadership. (ii) The foundation for the stewardship t/5
Nordic countries (range 1-4/100,000)3. Likewise, high in- program rests on two core strategies that are complemen- 4/1
/1
cidence rates (6.5/1,000 intensive care unit [ICU] admis- tary and include prospective audit with intervention and /2
5
sions)wererecentlyreportedfromamulticenterstudycon- feedback and formulary restriction and preauthorization. 7
9
4
ductedinIndia[26].Notably,theemergenceofmulti-drug- These strategies coupled with a strong educational effort 7
4
resistant(MDR;resistanttotwoormoreantifungalclasses) by clinical specialists have been shown to reduce unnec- by
g
strains of C. glabrata in the United States, Latin America, essary antimicrobial use and result in substantial antimi- u
e
s
Italy, France, and Denmark [27–35] and C. tropicalis, C. crobial cost savings. The effect of such efforts on antimi- t o
n
auris, and C. krusei in India [26] serve to emphasize the crobialresistanceislessclear.(iii)Multidisciplinarydevel- 0
3
importanceofregionalandlocalsurveillanceefforts. opmentofevidence-basedpracticeguidelinesincorporating A
p
InfectionwithCandidawasfoundtobesecondinrank- localmicrobiologyandresistancepatternsshouldbewidely ril 2
order(afterStaphylococcusaureus)inEuropeanandNorth available throughout the institution. Implementation of 01
9
AmericanICUsandCandidaispresentlythethirdleading these guidelines may be facilitated by provider education
causeofcatheter-associatedbloodstreaminfection(BSI)in and feedback on antimicrobial use and patient outcomes.
theUnitedStates[25,36].WhereasCandidainfectiongen- (iv)Antimicrobialorderformshaveproventobeaneffec-
erallyoccursinpatientswithalargenumberofcomorbidi- tivecomponentofantimicrobialstewardshipandcanfacili-
ties[2,4,13,37–40],theexcessmortality(49%)andlength tatetheimplementationofpracticeguidelines.Orderforms
of stay (LOS; 30 days) in hospital exceed that of most thatrequireclinicalindicationaswellasadefinedduration
other healthcare-associated infections (HAI) [7,20,24,41– of therapy may decrease antibacterial/antifungal courses
53]. Likewise, the costs associated with Candida infection and associated expenditures. Such order forms should not
(range $6,214 to $142,394 [US $] per patient) are among replace clinical judgement and requirements for renewal
thehighestofanyHAI[20,41,45,48,49,52–54].Improve- or extension of the course of treatment must be clearly
mentsinthediagnosisandmanagementofcandidalinfec- communicated in order to avoid inappropriate treatment
PfallerandCastanheira 3
interruption. (v) Streamlining or de-escalation of empiri- tifying those hospitalized individuals who are truly at the
cal therapy based on specific microbiological data (rapid highestriskforCandidainfectionandforwhomearlytreat-
species-leveldiagnosis,cultureresultsandantimicrobialre- ment with systemically active antifungal therapy will be
sistance profile) and elimination of redundant or unneces- of benefit [68]. This is an especially daunting task when
sarytherapycantargetthecausativepathogen,resultingin thecurrentdiagnostictests(bloodculture[BC],polymerase
decreased antimicrobial exposure and cost savings. While chainreaction[PCR],β-D-glucan[BDG])arequitevariable
important, such efforts to control antifungal usage have intermsoftimeliness,sensitivityandspecificity[9].BCsre-
beenhamperedbythesuboptimaldiagnosisofICusingcur- quire2–3daysofincubationuntilturningpositiveandboth
renttests.(vi)Animportantaspecttoconsiderinstreamlin- BDG-andPCR-basedmethodsaremostoftenperformedin
ingantimicrobialtherapyistheconversionfromparenteral reference laboratories with results available in days rather
to oral therapy (e.g., echinocandin to fluconazole) in pa- thanhours[9,19,41,56,58].Thelackofadequatediagnos-
tientswherethisisappropriate.Asystematicplanforsuch tic testing methods has resulted in overutilization of anti-
D
conversioncandecreasehospitalstayandhealthcarecosts. fungalagentsinmanyinstances[10,61,65,67,69].Whereas o
w
n
Implementationattheinstitutionallevelmaybefacilitated theuseofso-calledCandidascoresmayreducetheoverall lo
a
by development of clinical criteria and guidelines allow- populationofpatientsexposedtoempiricantifungalagents de
d
ing conversion to the use of oral agents. (vii) Healthcare [68,70–73],sucheffortsareimperfectwithsensitivitiesand fro
information technology and computer-based surveillance specificities ranging from 27% to 90% and 37% to 93%, m
h
can improve antimicrobial decision making by providing respectively [71,73]. There is a great need for more rapid, ttp
s
patient-specificmicrobiologyresultsandsusceptibility,tar- sensitiveandspecificdiagnostictestsforthediagnosisofIC ://a
c
get interventions, and track resistance patterns. (viii) Mi- andasanaidinantifungalstewardship[65,68]. a
d
e
crobiological support is essential to direct patient-specific Whereas timely administration of antifungal therapy m
ic
therapeutic interventions as well as assisting in infection is an important goal of antifungal stewardship [24,65], .o
u
control efforts. Implementation of newer immunological, overutilizationofantifungalagentsisoftenamuchlargeris- p.c
o
molecularandproteomictestmethodspromisetoenhance suewithimplicationsforantifungalresistance,excesscosts, m
/m
such efforts. It is the role of the clinical microbiologist to toxicityandadversedruginteractions[10,55,60,66,67,74– m
y
ensure that the correct testing methods are used and re- 77]. The administration of antifungal prophylaxis in pa- /a
sults reported and interpreted in a timely fashion in order tient populations where it has not been shown to be of rtic
le
tomaximizetheirclinicalimpact.(ix)Monitoringofboth value (e.g., echinocandin prophylaxis in the ICU setting) -a
b
s
process and outcome measures are important in assessing as well as misguided attempts to treat Candida coloniza- tra
c
the impact of stewardship efforts on patient care, antimi- tion of urinary and/or upper respiratory tracts leads to t/5
4
crobial use and resistance patterns. This is important in overuse of antifungal agents and possible resistance se- /1
order to evaluate the impact of antimicrobial stewardship lection [10,60,66,67,77,78]. The recognition of inappro- /1/2
5
as a measure of quality improvement and also as a means priate use of antifungal agents and early discontinuation 7
9
4
of providing feedback on the effectiveness of stewardship or de-escalation of drugs that are not required is an im- 7
4
effortstopatient-careproviders. portant role of antifungal stewardship [10,24,41,43,51– by
g
It is widely recognized that both the timing and selec- 53,55,57,61,63,65–67,69,74,79]. These efforts may be u
e
s
tion of antimicrobial therapy (right drug, right dose, right enhanced by rapid and sensitive diagnostic tests for t o
patient) are directly related to the mortality and costs of which the negative predictive value (NPV) is >99% [57– n 0
3
treatingHAIs.Byensuringthatbothtimelyandappropriate 59,61,80,81]. A
p
antimicrobial therapy is administered to the right patient, In addition to problems identifying those patients that ril 2
antimicrobialstewardshipshouldbothimprovepatientout- requireantifungaltherapy,thereareseveralproblemsinad- 01
9
come(mortalityandlengthofstay[LOS])andalsoreduce ministeringantifungaltherapythatimpacttheeffectiveness
the excess costs attributable to suboptimal antimicrobial andtherapeuticoutcomeaswellastheselectionpressures
use [55,61,66–70]. Notably, one of the major drivers for forresistance[12,24,27,28,55,60,74,75,82].Delaysinini-
antifungalstewardshipistherelativelyhighcostsandtoxi- tiation of therapy, selection of the most appropriate anti-
cityofantifungalagentswhichisoftengreaterthanthatof fungal agent to cover the indicated species, ensuring that
antibacterial agents [10,17–20,24,49,51,65–67]. It should the appropriate dose is administered and that therapy is
be recognized that a strong focus on limiting unnecessary administered for the appropriate duration, including early
antibacterialtreatmentreducesthepressureforfungalover- discontinuationoftherapythatisnotindicated,allhavea
growthandthustheriskforIC[40,50,63]. profoundimpactontheoutcomeoftherapyincandidiasis
Regarding the establishment of an antifungal steward- [13,16,20,24,65].Ineachinstancecorrectionofsuboptimal
shipprogram,oneissueofconcernisthedifficultyiniden- clinicalpracticesfallundertheumbrellaofmaintainingthe
4 MedicalMycology,2016,Vol.54,No.1
beststandardofcareforthepatientwhileatthesametime Table1.Candidemiariskfactorsforhospitalizedpatients.a
managing the excess costs that may be incurred [24,65].
RiskFactor Possibleroleininfection
Thestewardshipteamshouldadapttheguidelinesofexpert
panels such as the Infectious Diseases Society of America Antimicrobialagents Providevascularaccess
(IDSA)andtheEuropeanSocietyforClinicalMicrobiology (numberandduration)b andpromotefungalcolonization
Glucocorticoids Immunosuppression
andInfectiousDiseases(ESCMID)guidelinesfortheman-
Age(<1year,>70years) Immunosuppression
agementofcandidiasis[22,83,84]tothelocalpatientpop-
Chemotherapyb Immunosuppression
ulationandpracticepatterns[24].Effortstonotonlymini-
Mucosaldisruption
mizetheinappropriateadministrationofantifungalagents Malignancy Immunosuppression
touninfected(colonized)individualsbutalsotoensurethat Colonizationb Translocationacrossmucosa
the selected agent is likely to be active against the target Gastricacidsuppression Colonizationandtranslocation
species (local epidemiology) are the heart of stewardship Indwellingcatheterb Directvascularaccess
D
activities[75–77,85].Thefactthatfluconazoleisoftenad- Centralvenouscatheter Contaminatedproduct(deviceor o
w
ministeredatthewrongdose(toolow;e.g.,<12mg/kg/day infusate) nlo
Pressuretransducer a
for C. glabrata and <6 mg/kg/day for other species) and Port ded
forinsufficientdurationshouldbecorrectablethroughthe Totalparenteralnutrition Directvascularaccess fro
guidanceofthestewardshipprogram[12,76,85]. Hyperglycemia m h
The educational and monitoring role of the antifungal Contaminatedinfusate ttp
s
stewardship program is most effective when employing a Neutropenia(<500/mm3)b Immunosuppression ://a
multidisciplinaryapproach that includes input from infec- Surgery(abdominal) Routeofinfection ca
d
Mucosaldisruption e
tiousdiseases,hospitalepidemiologyandinfectioncontrol, m
Directvascularaccess ic
criticalcare,pharmacy,microbiology,hospitaladministra- .o
Mechanicalventilation Routeofinfection u
tionandselectedotherhealthcareproviders(e.g.,nursing, Renalfailure/hemodialysisb Routeofinfection p.c
o
oncology, transplant, and hospitalists) [24,65,74,86,87]. Immunosuppression m
/m
Suchdiverserepresentationsendsthemessagethatsteward- Solidorgantransplant Routeofinfection m
y
shipisconsideredanimportantefforttoimprovethecare Mucosaldisruption /a
ofpatients.Whereastheprocessofformularymanagement Directvascularaccess rtic
le
isfamiliartomostphysiciansandpharmacists,thisisonly Immunosuppression -a
b
HospitalorICUstay Exposuretopathogens s
part of the mission of antifungal/ antimicrobial steward- Exposuretoadditionalriskfactors trac
ship programs [24,88,89]. Certainly both pre-prescription Severityofunderlyingillness Invasiveprocedure t/5
4
approvalorpost-prescriptionreviewandfeedbackarecom- /1
monpracticesbuttheseapproachesmustbehandledwith aCompiledfromrefs2and8. /1/2
bIndependentriskfactor. 5
care not only to identify deficiencies in prescribing prac- 7
9
4
tices but also to educate prescribers on the importance of 7
4
candidiasis and the appropriate use of antifungal agents opment of treatment guidelines for fungal infection in the by
g
[24,74,78,89]. Ideally these efforts will build trust and an institution.SimilarlyGuarascioetal.[77]haveshownthat u
e
open dialog between the stewardship team and physician anactiveantifungalstewardshipeffortresultedintwofewer st o
n
prescribers[89]. days of echinocandin therapy with a savings of $1,013 0
3
The stewardship team must identify the patient pop- (US$)perpatient. A
p
ulation at risk, taking into account both risk fac- ril 2
tors and prior antifungal exposure as well as associ- 01
Riskfactors 9
ated cost considerations [39–41,43,51–53,57,80,90–92].
Whereas several studies have shown an economic advan- Thelackofspecificclinicalfindingsandslow,insensitivedi-
tage when effective antibacterial stewardship programs agnostictestingcomplicatetheearlyrecognitionandtreat-
are in place [61,63,64,69,79,81,87–89,93], most antifun- ment of candidiasis [65,68]. Most experts recommend the
gal stewardship efforts have shown improvement in the use of clinical risk factors to identify patients who may
process of managing fungal infections but not necessarily benefitfromprophylacticorearlyempiricaltherapyinthe
an economic benefit [10,18,24,41,43,52,53,55,65,67,74– properclinicalsetting[40,68,95](Table1).Unfortunately,
76,82,85–87,90,94].Notably,asinglecenterstudybyStan- thepredominantriskfactorsforcandidiasisarecommonia-
difordetal.[66]documenteda$2,251,976(US$)reduction trogenicand/ornosocomialconditions[8,57,68].Thevar-
inantifungalcostsovera3-yearperiodwiththeinstitution iousCandidascoreshavebeenshowntoprovidesomeen-
of an antimicrobial stewardship program and the devel- richment of candidiasis incidence for populations at risk;
PfallerandCastanheira 5
Table2.Riskforcandidemiaisacontinuum.a Table 3. Risk for candidemia in intensive care unit (ICU)
(cid:2) patients.
Generalriskfactorsuponadmissiontohospital
-Hematologicmalignancy Calculatedriskofinfectionbasedupon
-Neutropenia baselinerisksof1%,2.5%,and5%inICU
-Abdominalsurgery Exposure patientswithspecificexposures
-Solidorgantransplant
-Prematureinfant Baseline 1% 2.5% 5%
-Olderadult(>70yearsofage) 4antibiotics 7% 17% 35%
(cid:2) 4antibioticsplus 40% 65% 80%
Specificexposuresthatfurtherincreaserisk(ORoddsratio)
colonization
-IntensiveCareUnitstay>7days(OR,9.73)
6antibioticsplus 100% 100% 100%
-Centralvenouscatheter(OR,7.23)
colonizationplus
-Dialysis(OR,18.13)
hemodialysis
-Antibiotics(OR,1.73perantibioticclass) D
o
-Totalparenteralnutrition(OR,8.87) Adaptedfromref40. wn
-Colonization(OR,10.37) loa
hemodialysis [40,44,96]. Hospitalization in the ICU pro- d
e
d
aCompiledfromrefs44and96. vides the opportunity for transmission of Candida among fro
patients and has been shown to be an additional indepen- m
h
however, they are only 50% sensitive, which is why they dent risk factor (10-fold increase in risk) [96]. When two ttp
s
are limited in use to clinical trial recruitment rather than or more of these risk factors are present, the probability ://a
c
routinepatientcaresettings[68,70–72].Additionalmean- ofinfectionincreasesevenfurther.Thus,WenzelandGen- a
d
e
ingful stratification by independent risk factors will be re- nings [40] have demonstrated that if a patient in the ICU m
ic
quired to identify those high-risk patients who would de- had exposure to four different antibiotics, his or her risk .o
u
rive maximal benefit from early therapeutic interventions ofcandidemiawouldbeapproximately35%givenabase- p.c
o
[40,57,96]. line frequency of infection in the ICU of 5% (Table 3). m
/m
Itisimportanttounderstandthattheriskforcandidiasis However,afteraddingjustoneadditionalriskfactor(e.g., m
y
inthehospitalisacontinuum[8,40,44](Table2).Certain colonization of another site such as urine or wound) the /a
individuals are clearly at increased risk for acquiring can- riskjumpstoapproximately80%(Table3).Thus,analysis rtic
le
didemia(oranyothernosocomialinfection)duringhospi- ofriskfactorsmayhelpguidetheapplicationofantifungal -a
b
s
talizationasaresultoftheirunderlyingmedicalconditions: therapytothosepatientswhoaremostlikelytobenefitfrom tra
patientswithhematologicalmalignanciesand/orneutrope- it[40,68].Havingsaidthisitisimportanttorecognizethat ct/5
nia,thoseundergoinggastrointestinalsurgery,solidorgan despitetheprovenefficacyoftheechinocandinsinthetreat- 4/1
transplant recipients, premature infants and adults older ment of IC, the available evidence does not support their /1/2
5
than 70 years of age (Table 2). Among patients with can- useasprophylaxisintheICUsetting[72].Riskstratification 7
9
4
didiasis the mean time to onset of infection is 22 days of isalsoimportantforselectingpatientstotestforCandida 7
4
hospitalization [8]. Thus, candidiasis typically affects in- biomarkersasameansofinitiatingearlypreemptivether- by
g
dividuals with considerable comorbidities who have pro- apyevenintheabsenceofclinicalsignsandsymptoms[59]. u
e
s
longedhospitalization. Patients identified by these risk stratification tools should t o
n
Within the high risk groups of patients, specific addi- haveimprovedoutcomes;however,theseverityoftheun- 0
3
tionalexposureshavebeenrecognizedasindependentrisk derlying disease and other co-morbidities complicate this A
p
factors by multivariate analysis of data from matched co- process and influence mortality independent of antifungal ril 2
hortstudies[8,40,96](Table2).Theseincludethepresence therapy. Unfortunately at the present time there are still a 01
9
ofvascularcatheters,exposuretobroad-spectrumantibac- numberofinfectedindividualswhoarenottreated,anda
terialagents,renalfailure,mucosalcolonizationwithCan- largergroupofuninfectedindividualsreceivingcostlyand
didaspp.,prolonged(≥7days)ICUstay,andreceiptoftotal unnecessaryantifungaltherapy[68,70–72].
parenteralnutrition(TPN).Comparedwithcontrolpatients
withoutthespecificriskfactorsorexposures,thelikelihood
Local epidemiology: Species identification,
of these already high-risk patients contracting candidiasis
andantifungalresistance
in hospital is approximately 2 times greater for each class
ofantimicrobialagentstheyreceive,7timesgreaterifthey Inordertoconductantifungalstewardshipeffectively,pro-
have a central venous catheter (CVC), 10 times greater if viding guidance and information to clinicians faced with
Candida has been found to be colonizing other anatomi- diagnosing and treating nosocomial candidiasis, the mem-
calsites,and18timesgreaterifthepatienthasundergone bers of the antifungal stewardship team must have a firm
6 MedicalMycology,2016,Vol.54,No.1
Table4.SpeciesdistributionofCandidaisolatesfrompatients mallysterilesites[100].Unfortunately,thequestion“Why
withcandidemia:resultsfromsentinelandpopulation-based identifyCandidatospecies?”isstillposedbysomehealth-
surveillance. care providers and laboratorians [78,101]. Whereas lack
of species identification might have been reasonable in
%oftotalbysurveillance
the past when C. albicans was the dominant species and
program(No.ofisolates)
the choice of antifungal therapy was limited to ampho-
SENTRYa PATHb CDCc tericin B [102,103], the present day situation is much
Species (860) (3,648) (2,209) more complicated [104,105]. There are now more infec-
tions with non-C. albicans species in most hospitals car-
C.albicans 47 42 41
C.glabrata 18 27 27 ing for high risk patients and the choice of antifungal
C.parapsilosis 18 16 18 agents now spans several different classes and formula-
C.tropicalis 11 9 9 tions [105–111]. The increase in non- C. albicans infec-
D
C.krusei 1 3 2 tions is considered to be largely due to the widespread o
w
Other 5 3 3 n
use of fluconazole which selects for those species that are lo
a
aPfalleretal.[97]. intrinsically less susceptible to this agent than C. albi- de
d
bPfalleretal.[98]. cans [3,5,12,22,43,60,65,67,89,90,94,106,107,111–115]. fro
cClevelandetal.[5]. Furthermore, species-specific resistance profiles are now m
h
well-recognized[8,112].Itisnowclearthattheinvitropat- ttp
s
understandingofthelocalepidemiology(e.g.,thefrequency terns of antifungal susceptibility vary substantially among ://a
c
of occurrence as well as the antifungal susceptibility pro- different Candida spp. (Table 5) and the IDSA and a
d
e
file of each species encountered in the hospital) [24,65]. ESCMID guidelines for the treatment of candidiasis rec- m
ic
In many institutions this information is readily available ommendthatspecies-levelidentificationbeusedasasurro- .o
u
from the microbiology laboratory and should be summa- gate for antifungal susceptibility testing for selecting em- p.c
o
rized and distributed to the antifungal stewardship team pirical antifungal therapy [22,83,84]. Most recently the m
/m
as well as to clinicians that care for high risk patients Clinical and Laboratory Standards Institute (CLSI) and m
y
[74,87,89]. In situations where such data are not avail- the European Committee on Antimicrobial Susceptibility /a
able, efforts should be made to collect local information Testing (EUCAST) have published species-specific clinical rtic
le
andintheinterimdatafromnationalandregionalsurveys breakpoints for the triazoles and echinocandins as well -a
b
s
may be useful [5,94,97,98]. In the United States, Europe, as species-specific epidemiological cutoff values (ECVs or tra
c
andAsia,bothsentinelandpopulation-basedsurveyshave ECOFFs) that help predict decreased susceptibility and t/5
4
beenconductedoverseveralyearsdurationandmayserve potential resistance among those species for which clini- /1
asabaselineforcomparisonwithlocalepidemiologicdata cal data are unavailable [100]. C. albicans and C. tropi- /1/2
5
[3,6,7,23,26,34,38,97,99](Tables4and5). calis are both susceptible to all of the available systemi- 7
9
4
Most institutions that care for high risk patients of- callyactiveantifungalagentsincludingfluconazoleandthe 7
4
fercomprehensivemicrobiologyservicesthatincludeboth echinocandins [97,116,117]. Resistance to both the azole by
g
species-level identification as well as antifungal suscepti- and echinocandin classes is very unusual for both C. albi- u
e
s
bility testing of Candida spp. from blood and other nor- cansandC.tropicalis.Thusthemorecost-effectiveagent, t o
n
0
3
Table5.Candidaspeciesantifungalsusceptibilityprofile.a Ap
SusceptibilitycategoryasdeterminedbyCLSIInterpretiveCriteriab ril 20
1
9
Species AMB FLC ITR VOR Echinocandins
C.albicans S S S S S
C.tropicalis S S S S S
C.parapsilosis S S S S S/?c
C.glabrata S/NS SDD/R SDD/R S/NS S/R
C.krusei S/NS R SDD/R S S
aAbbreviations:CLSI,ClinicalandLaboratoryStandardsInstitute;AMB,amphotericinB;FLC,fluconazole;ITR,itraconazole;VOR,voriconazole;S,susceptible;
NS,non-susceptible;SDD,susceptibledosedependent;R,resistant.
bPfallerandDiekema,(100)
cMICsforechinocandinsandC.parapsilosisareelevatedcomparedtootherspecies.Fluconazoleisthepreferredagentsforthisspecies.
DatacompiledfromPappasetal.[22]andPfallerandDiekema[8].
PfallerandCastanheira 7
fluconazole, may be used in most situations reserving the C. tropicalis causes infection in oncology patients receiv-
echinocandins for the more seriously ill and unstable pa- ing chemotherapy [8,108,111]. Colonization of high risk
tient [21,22,112]. Likewise, C. glabrata and C. krusei are patientswithcertainspeciesoftenpredictssubsequentBSI
groupedtogetherbasedontheirdecreasedsusceptibilityto with those species [8]. This has been demonstrated with
fluconazole[22,112,117].TheIDSAandESCMIDbothrec- C.glabrata,C.tropicalis,andC.kruseiinHSCTrecipients
ommendthatanechinocandinbeusedforinitialtreatment [123,124].
ofinfectionsduetoeitherofthesespeciesbasedontheex- One of the reasons that the question “Why identify
cellentfungicidalactivityoftheseagentsagainstthesetwo Candida to species?” has been posed is that the conven-
species[22,83,84].De-escalationtofluconazolemaybeap- tionalmethodsforspeciesidentificationareslow,cumber-
propriateforinfectionswithC.glabratabasedoninvitro some, often inaccurate and cannot provide species iden-
susceptibilityresultsbutisneverappropriateforC.krusei tification within the critical 12–24 h treatment window
[21,22,65,90,94]. Finally, C. parapsilosis requires specific [125–127]. Conventional methods for yeast identification
D
identificationforseveralreasons[118]:(i)duetodecreased include the germ tube test, morphology on chromogenic o
w
n
susceptibilitytotheechinocandins,itisrecommendedthat and cornmeal agar, temperature tolerance, and biochemi- lo
a
fluconazole be used as initial therapy for C. parapsilosis calmethodssuchasVitek(bioMerieux),API(bioMerieux), de
d
infections [21,22]. As with C. albicans and C. tropicalis, MicroScan (Beckman-Coulter) and others [125,127,128]. fro
C. parapsilosis is usually susceptible to fluconazole [117]; These tests require isolated colonies and incubation times m
h
(ii)C.parapsilosisisnotoriousforcausingcatheter-related of48to72hbeforeaspeciesidentificationisobtained.Even ttp
s
BSIsandbothIDSAandESCMIDemphasizethatcatheters rapid“spot”testsforC.albicans(e.g.,BactiCardCandida ://a
c
alwaysberemovedinC.parapsilosisinfections[22,83,84]; [Remel],AlbiQuick[Hardy])andC.glabrata(e.g.,Rapid a
d
e
(iii)whenC.parapsilosisisfoundtobeacauseofBSI,one TrehaloseAssimilation[Remel],RapidTrehalase[Rosco]) m
ic
mustconsiderthattherehasbeenalapseinpropercatheter require isolated colonies on agar medium before applying .o
u
carethatmayrequireremedialinstructionofhealthcareper- therapidtestforidentification(delayofatleast24h)[128]. p.c
o
sonnelandthepatientasappropriate[8,118].Thisspecies Notably, these phenotypic methods may mis-identify rare m
/m
frequently gains access to the bloodstream via contam- or emerging species of Candida with clinically impactful m
y
ination of the catheter hub and readily forms a biofilm consequences [23,125,127]. A very recent example is the /a
withinthelumenofthecatheter[113,119,120].Formation misidentificationoftheMDRspeciesC.aurisasC.haemu- rtic
le
ofbiofilmsconferssignificantresistancetoantifungalther- lonii or C. famata by the Vitek 2 and other phenotypic -a
b
s
apy resulting in persistent infections despite what should identificationsystems[129]. tra
c
beadequateantifungaltherapy[118].Whereasbiofilmfor- Morerecently,severalnewapproachestoyeastidentifi- t/5
4
mationbyC.parapsilosisiswidelyrecognized,itisnotthe cationhavegreatlyimprovedthetimelinessandaccuracyof /1
onlyspeciesofCandidathatiscapableofformingbiofilms Candidaspeciesidentification[56,125,127].Theseinclude /1/2
5
onimplantedbiomaterials[121,122]. peptidenucleicacid(PNA)-fluorescentinsituhybridization 7
9
4
(FISH), sequence-based identification, and matrix-assisted 7
4
Speciesidentification laser desorption ionization-time of flight mass spectrome- by
g
Although the genus Candida contains over 200 different try(MALDI-TOF-MS)[56,130].Thesemethodshavebeen u
e
s
species, there are five major species (C. albicans, C. trop- applied directly to blood cultures and agar-based cultures t o
n
icalis, C. parapsilosis, C. glabrata, and C. krusei) that ac- and provide highly accurate identifications within 1 to 2h 0
3
count for 95% to 97% of human infections (Table 4). postculture[56,93,130,131]. A
p
In most instances the rank order is C. albicans > C. ThePNA-FISHtests(AdvanDx,Woburn,MA)arebased ril 2
glabrata > C. parapsilosis > C. tropicalis > C. krusei; on a fluorescein-labeled PNA probe that specifically de- 01
9
however, the exact distribution may vary by geographic tectsC.albicans,C.tropicalis,C.parapsilosis,C.glabrata,
location and risk group [114,116,117]. For example, the andC.kruseiinBCsbytargetingspecies-specificrRNAse-
fluconazole-resistantspeciesC.glabrataandC.kruseicause quences. Recent modifications to the probes and reagents
a disproportionate number of infections in hematopoietic have resulted in a second generation test (QuickFISHTM)
stemcelltransplant(HSCT)recipientswhereazoleprophy- that shortens the time to results from 90 minutes to 30
laxis is common [8,98,108,114]. C. parapsilosis, a species minutes. The test has been shown to have excellent sensi-
found on the skin of both patients and healthcare work- tivity (99%), specificity (100%), positive predictive value
ers,causescatheter-relatedBSIsandisespeciallyprominent (100%)andnegativepredictivevalue(99.3%)[132].This
amongpatientsreceivingTPNaswellasinneonates[118]. approach may provide a time savings of 24 to 48 hours,
C.glabrataisamongthemostcommonspeciesassociated compared with conventional laboratory methods used for
withBSIamongthosegreaterthan70yearsofage,whereas identification.
8 MedicalMycology,2016,Vol.54,No.1
Amplification-basedmethodsareincreasinglybeingap- group,therewassignificantreductionintheusageofcaspo-
plied to the post-culture identification of Candida and fungin(de-escalationtofluconazole)withacorresponding
other yeasts [56,69,125]. Multiplex PCR platforms have decrease in antifungal costs of $ 1,978 (US $) per patient
beendevelopedfortheidentificationofCandidaspeciesin [135].Theoverallcostsavingsinreducingcaspofunginus-
positiveBCsamples[133].TheFilmArrayTMBCidentifica- age surpassed the cost of the PNA-FISH test (net savings
tion panel (BioFire, Salt Lake City, UT) and the xTAGTM of$1,729[US$]perpatient)and ledtothedevelopment
fungal analyte-specific reagent assay (Luminex Molecular of straightforward hospital-specific algorithms [135]. The
Diagnostics, Toronto, Canada) have demonstrated sensi- disadvantages of these post-culture approaches for the di-
tivities and specificities of 100% and 99%, respectively, agnosis of IC is that they are still dependent on a positive
for the five most common species of Candida [56,133]. BC,whichmaybenegativein>50%ofICcases[58].None
TheFilmArrayapproachprovidesfullyautomatednucleic ofthesemethodsaresensitiveenoughtoreliablydetectand
acid extraction, amplification and detection and has been identify Candida directly from clinical specimens but the
D
FDAclearedforpost-cultureidentificationofbacteriaand improved accuracy and time to identification has clearly o
w
n
Candidaspecies. helpedlaboratoriestoprovidespecies-levelidentificationin lo
a
Oneofthemostimportantadvancesinthepost-culture amoreclinicallymeaningfultimeframe[56]. de
d
identificationofbacteriaandfungiisthatofMALDI-TOF fro
MS [56,93,127,128,130]. MALDI-TOF MS uses species- Antifungalresistance m
h
specificpatternsofpeptidesandproteinmassestoprovidea Although antifungal resistance is not as prevalent as an- ttp
s
rapidandreliablemethodfortheidentificationofCandida, tibacterialresistance,theoveruseofineffective,orunneces- ://a
c
non-Candida yeasts, and some molds [56,93,128,130]. sary,antifungaltherapyisadrivingforcefortheemergence a
d
e
Studies have shown that this method is able to accu- ofantifungalresistanceinCandidaspp.justasitisforbac- m
ic
rately and rapidly (10 min) identify Candida species from teria [18,27,28,60,136]. Indeed the CDC has specifically .o
u
positive cultures, with a high concordance (>90%) in notedtheincreasingincidenceofCandidainfectionsdueto p.c
o
comparison to both conventional and molecular methods azole-andechinocandin-resistantstrainsandconsidersitto m
/m
[9,56,93,128,130]. bea“serious”publichealththreatthatmustbeaddressed m
y
Thesemolecularandproteomicapproachesforidentifi- throughimproveduseofantifungalagents[137]. /a
cationofCandidafrompositiveculturesimprovethetime Presently, there are emerging resistance issues in three rtic
le
to identification when compared to conventional meth- common species of Candida: C. glabrata, C. parapsilosis, -a
b
s
ods and may be useful in antifungal stewardship inter- and C. tropicalis. C. glabrata is a leading human fun- tra
c
ventions promoting optimal antifungal therapy with the gal pathogen that causes life-threatening infections and t/5
4
mostcost-effectiveantifungalagents,resultinginimproved poses a challenge to antifungal therapeutic options due /1
outcomes and significant antifungal savings for hospitals to its reduced susceptibility to the azole antifungal agents /1/2
5
[9,24,41,56,93].Acostminimizationmodelwasdeveloped and the ability to develop resistance to both azoles and 7
9
4
by Alexander et al. [134] to assess cost savings associated echinocandins [29]. Resistance to fluconazole now ap- 7
4
with implementation of the PNA-FISH test in a hospital proaches 30% of all C. glabrata isolates in many areas of by
g
with a rate of 40% for C. albicans candidemias and in theUnitedStatesandechinocandinresistancerangesfrom u
e
s
which caspofungin was used over fluconazole for empiric 3% to 18% in institutions caring for high risk patients t o
n
treatmentofIC.Intheirstudytheypredictedthattheuseof [18,27,28,60,136].TheSENTRYsurveillanceprogramhas 0
3
thePNA-FISHtestwouldresultinacostsavingsofapprox- documentedasteadyincreaseinboththefrequencyofiso- A
p
imately$1,800(US$)perpatientfromreducedcaspofun- lation of C. glabrata from BCs as well as an increasing ril 2
gin use (switch to fluconazole in patients infected with C. resistance to both fluconazole and echinocandins in the 01
9
albicans),despitethefactthatlaboratorycostsforperform- United States over the past 19 years [29,32,138]. Similar
ing the PNA-FISH test ($ 82.72 [US $] per test) exceeded findingshavebeenreportedfrompopulation-basedsurveil-
thosefortheC.albicansscreentest($2.83[US$])orthe lance in Denmark but not in other European countries
Germtube test($4.42 [US$]).A subsequent study atthe [3,23]Recently,datafromtheCDCdemonstratedasteady
University of Maryland [135] used clinical data to show increase in echinocandin resistance among BSI isolates of
the effect of PNA-FISH testing for C. albicans and vali- C. glabrata in the Atlanta and Baltimore metropolitan ar-
dated the decision model of Alexander et al. [134]. The eas [31]. Notably, 14.8% of fluconazole-resistant isolates
Marylandinvestigatorsfoundthat43%ofcandidemiasin ofC.glabratawerealsoechinocandin-resistantand36.2%
their hospital were due to C. albicans and that the most of echinocandin-resistant isolates were also fluconazole-
pronounced effects of the PNA-FISH test was on caspo- resistant. Co-resistance to both azoles and echinocandins
funginusageinpatientswithC.albicansfungemia.Inthis has also been documented in C. glabrata isolates from
PfallerandCastanheira 9
both single center [27,28,136] and multicenter antifungal from all regions of the country [117]. Notably, a recent
surveillance programs [33,139]. Emergence of azole- and surveyfoundthatincontrasttopreviousyears,echinocan-
echinocandin-resistanceinotherpartsoftheworldisnotas din resistance was detected among U.S. C. tropicalis BSI
extensiveasintheUnitedStates;however,increasedratesof isolates from 2013[142]. Previous reports have shown a
resistancetobothclassesofantifungalagentsamongnon- step-wiseprogressionofechinocandinresistanceassociated
C.albicansspecieshasbeennotedinDenmarkandFrance, with the development of FKS mutations in isolates of C.
andmostrecentlyinIndia[26,34,35]. tropicalis from patients being treated with an echinocan-
Among the different Candida species, C. glabrata ap- din [143–145]. Recent data from India indicates that C.
pears to be unique in its ability to acquire and express tropicaliswasthemostfrequentcauseofcandidemiainpa-
mutations that result in phenotypic and clinical resistance tients in the intensive care unit (ICU) and is an emerging
[29,30]. This may be due to the haploid nature of the or- MDR(resistancetofluconazoleandechinocandins)species
ganism resulting in the ability to rapidly express a vari- ofCandidainthatcountry[26].
D
ety of resistance mutations [27–30,136,139].Exposure to Thedevelopmentofresistancetoazolesandechinocan- o
w
n
fluconazole reliably induces CDR efflux pumps resulting dinsamongthreecommonspeciesofCandidaiscausefor lo
a
in pan-azole resistance [29,112]. Similarly, exposure to concern. Because genes encoding for antifungal resistance de
d
echinocandins has been shown to be a predictor of mu- in Candida are not passed from organism-to-organism fro
tations in the FKS genes encoding for the glucan syn- [115,146],controlofsuchresistanceshouldbemoreeasily m
h
thase enzyme complex (target for echinocandin activity) addressed than is the case with bacteria. Antifungal resis- ttp
s
andthusechinocandinresistanceinthreemajorU.S.trans- tance in Candida is clearly related to the exposure of in- ://a
c
plantcenters[27,28,136].Ineachcaseelevatedechinocan- fecting and colonizing strains to specific antifungal agents a
d
e
dinMICsandacharacteristicFKSmutationcorrelatedwith [27,28,60,115,136,147]. As such the efforts of antifun- m
ic
echinocandintreatmentfailure. gal stewardship to reduce inappropriate use of antifungal .o
u
C. parapsilosis is most notable for causing BSI in agentsshouldalsoimpacttheemergenceofresistanceata p.c
o
neonates and patients receiving TPN [98,118]. Infection giveninstitution.Applicationofrapidspecies-specificdiag- m
/m
with C. parapsilosis is almost always associated with in- nostic tests should make these efforts even more effective m
y
dwelling vascular catheters [118]. The decreased suscepti- allowingspecificantifungaltherapytobeadministeredonly /a
bility of C. parapsilosis to echinocandins is a well-known tothosepatientsthatareinfected. rtic
le
concern [117], with some centers reporting a decreased -a
b
s
prevalence of C. albicans in favor of C. parapsilosis as a Diagnosis trac
cause of candidiasis in patients exposed to echinocandins t/5
4
[91]. In light of these concerns both IDSA and ESCMID It is widely recognized that early diagnosis of candidiasis /1
have recommended the use of fluconazole coupled with isdifficult[58,59,68].Theclinicalsignsandsymptomsare /1/2
5
prompt catheter removal in patients with C. parapsilosis non-specificandoftenappearlateinthecourseofinfection. 7
9
4
BSI [22,83,84]. Whereas resistance to fluconazole has not Given the critically ill nature of most high-risk patients, 7
4
beenaconcernwithC.parapsilosis[97,116],areportfrom invasivediagnosticproceduresmaybeconsideredtoorisky by
g
Finland suggested that fluconazole resistance in C. parap- andtheentirediagnosticprocessisnegativelyimpactedby u
e
s
silosis may emerge following drug pressure in the form of thelackofsensitiveandminimallyinvasiveassays[9,56]. t o
n
fluconazole prophylaxis [140]. Most recently the flucona- 0
3
zole resistance rate among US isolates of C. parapsilosis Physicalexamination A
p
was 4.0% for the time period 2006–2011 (range 0.0% to With regard to the physical examination of patients at ril 2
16.9%)[117]. high risk for Candida infections there are a few impor- 01
9
C. tropicalis is generally susceptible to both azoles and tant features that should be kept in mind. In the non-
echinocandins [5,117], and the use of these agents has neutropenic patient a dilated eye examination to detect
beenassociatedwithadecreaseinincidenceofBSIsdueto Candidaendophthalmitiscanservetoguidetherapyinpa-
C. tropicalis in US cancer centers [108,111]. It must be tientswithestablishedcandidemiaandisaprocessmeasure
noted, however, that resistance to fluconazole and other thatismonitoredinseveralstewardshipefforts[22,75].In
azolesappearstobeincreasingamongclinicalisolatesofC. some instances intravitreal antifungal therapy and/or vit-
tropicalisoutsideoftheUnitedStates,withrangesof7%in rectomy may be indicated. Furthermore, evidence of eye
Denmark[3]to40%inJapan[141].IntheUnitedStates, involvement should prompt the addition of an antifun-
fluconazoleresistanceamongisolatesofC.tropicalisranges gal agent that has ocular penetration, such as flucona-
from2.4%to4.8%withcross-resistancebetweenflucona- zoleorflucytosine,especiallyifthepatientisbeingtreated
zole, posaconazole, and voriconazole detected in isolates with an echinocandin, a class of agents for which ocular
10 MedicalMycology,2016,Vol.54,No.1
penetrationislimited[21,22].Dailyexaminationoftheskin Among the potential biomarkers that may be detected by
mayalsoreveallesionssuggestiveofhematogenousdissem- various methods, there are several that are commercially
ination [148]. Biopsy of such lesions can provide a rapid availableintheUnitedStatesorEuropeeitherassendout
and definitive diagnosis of candidiasis (or other infectious tests (reference laboratory) or in a kit format to be per-
etiologies)[149,150].Giventheseriousnatureofcandidal formed on-site in the hospital laboratory (Table 6). The
endocarditis,auscultationoftheheartformurmursshould biomarkers and associated test methods to be covered in
also be performed as a matter of routine [22,83,84]. Fi- this review are the Fungitell β-D-glucan (BDG; Associates
nally,examinationofanysitesofintravascularcatheteriza- of Cape Cod, Inc.) test, the Platelia mannan/anti-mannan
tion,andconsiderationofearlyremovalinsepticpatients, (BioRad Laboratories) immunoassays, two real-time PCR
is important given the frequency of Candida as a cause of assays available from Quest (www.questdiagnostics.com)
catheter-associatedinfection[21,22]. and Viracor (www.viracoribt.com) reference laboratories,
respectively,as well as the SeptiFast real-time PCR test
D
Bloodcultures (Roche Molecular Systems) and the T2Candida panel o
w
n
Blood cultures (BCs) remain an established approach to (T2Biosystems)[151,154,159]. lo
a
the diagnosis of candidiasis [22,83,84]. This is despite BDG (1-3, β-D-glucan) is an important component of de
d
the fact that BCs have always been considered to be too the cell wall of Candida, Aspergillus, and many other fro
slowandinsensitivetoserveasanearlydiagnosticmethod pathogenic fungi, and thus is nonspecific [160]. Although m
h
[56,58,62,151].Itisincreasinglyapparentthatasmanyas BDGisnotimmunogenic,thefactthatitcanbefoundcir- ttp
s
one-thirdofpatientswithcandidiasisneverhaveapositive culatinginthebloodstreamofpatientswithinvasivefungal ://a
c
BCandevenwhenpositive,species-levelresultsmaynotbe infection(IFI)hasbeenexploitedforusediagnosticallyasa a
d
e
availablefor48to72horlonger[16,58,152].Notably,ina surrogatemarkerforinfection[56,68].TheFungitellassay m
ic
reviewof415autopsy-provencasesofcandidiasis,Clancy is a commercially-available CE-marked and FDA-cleared .o
u
and Nguyen [58] demonstrated that BCs were positive in assayforthedetectionofBDGinserum[56,160].Thede- p.c
o
only38%ofcases.ThislowyieldofBCswasconfirmedby tectionsystemisbasedontheactivationofaBDG-sensitive m
/m
Avnietal.[153]whoreportedapooledBCpositivityrate proteolytic coagulation cascade, the components of which m
y
of 38% in a meta-analysis of 10 studies for the diagnosis are purified from the horseshoe crab [56]. The assay can /a
ofIC.Culturesofbloodandotherclinicalspecimensmay measurepicogramquantitiesofBDGandhasbeenusedto rtic
le
also be rendered falsely negative by the use of prophylac- demonstratethepresenceofthepolysaccharideintheserum -a
b
s
tic or empiric antifungal therapy further confounding ef- ofpatientswithcandidiasisandaspergillosis.Thetestdoes tra
c
fortstoestablishafirmdiagnosis[154,155].Despitethese notdetectcryptococcosisormucormycosis(organismslack t/5
negative features, BCs remain at the heart of care guide- 1-3,β-D-glucan),nordoesitprovidespecies-levelidentifi- 4/1
linesforcandidiasisinhospitalizedindividuals[22,83].Be- cationforeitherCandidaorAspergillus[56].TheBDGtest /1/2
5
causecontemporaryBCmethodsdemonstratevariablesen- has been associated with a large number of false-positive 7
9
4
sitivity,especiallyatlowconcentrationsofCandidainthe results in high risk patient populations, limiting its value 7
4
blood sample, current practice is to serially collect mul- forscreeningpurposes[58,68,160].Causesoffalse-positive by
g
tiple aerobic and anaerobic BC specimens over 24 to 48 BDG results include Gram-positive BSI, excess manipula- u
e
s
h [9,75,128,156]. It should be noted that the fungal BC tion of the sample prior to testing, hemolysis, hemodialy- t o
n
bottlesavailableforboththeBacT/Alert(bioMerieux)and sis with cellulose membranes, patients treated with intra- 0
3
Bactec (Becton Dickinson) BC systems are superior to the venous immunoglobulins, albumin, coagulation factors or A
p
standardaerobicBCbottlesfordetectionofCandidaspp. plasmaproteinfactor,orpatientsexposedtogauzeorother ril 2
[157,158].Thisisespeciallyimportantforthedetectionof materialsthatcontainglucans[58,68,160].Arecentmeta- 01
9
C. glabrata with the Bactec system [3,23,157]. It is now analysisof16studiesmeasuringserumorplasmaBDGfor
understoodthattheinformationrequiredtolimitmortality thediagnosisofcandidiasisreportedpooledsensitivityand
and the emergence of antifungal resistance is time-critical specificity values of 75.3% and 85.0%, respectively [160]
and as such rapid culture-independent diagnostic tests are (Table 6). Although the BDG test may be performed in
required to complement BCs in the management of high a hospital-based laboratory, it is a send out test for the
riskpatients[56,58,62,81,151]. vastmajorityofinstitutionsresultinginaturn-aroundtime
(TAT)forresultsmeasuredindaysratherthanhours.
Culture-independentdiagnostictests Despite a long history of serologic tests for Candida
Culture-independent tests for candidiasis may be used as antigens and antibodies, the only immunologic markers
biomarkers to assess the risk of having candidal infection that have shown any utility for Candida diagnosis are
thereby facilitating preemptive therapy [18,56,58, 59,62]. anti-mannan antibodies and mannan antigen [56,161].