A rare case of Candida glabrata spondylodiscitis: case report and literature review

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Review

A

rare

case

of

Candida

glabrata

spondylodiscitis:

case

report

and

literature

review

Manfredi

Gagliano

a,

*

,

Costanza

Marchiani

a

,

Giulia

Bandini

a

,

Paolo

Bernardi

a

,

Nicolas

Palagano

a

,

Elisa

Cioni

a

,

Martina

Finocchi

a

,

Silvia

Bellando

Randone

b

,

Alberto

Moggi

Pignone

a

ExperimentalandClinicalMedicineDepartment,DivisionofInternalMedicine,AOUCareggi,Florence,Italy

b

ExperimentalandClinicalmedicineDepartment,DivisionofRheumatology,AOUCareggi,Florence,Italy

ARTICLE INFO Articlehistory:

Received22October2017

Receivedinrevisedform29December2017 Accepted5January2018

CorrespondingEditor:EskildPetersen, Aar-hus,Denmark. Keywords: Candidaglabrata Spondilodyscitis Anidulafungin Debridement ABSTRACT

Background:Spondylodiscitisisaninfectionofthevertebralcolumn,theincidenceofwhichisincreasing

duetoanincreaseinthesusceptiblepopulationandimprovedascertainment.Thisdiseasehasbeen

associatedwithawiderangeofmicroorganisms.Fungalspondylodiscitisisuncommon(0.5–1.6%)and

stronglyassociatedwithimmunosuppressionanddiabetes(Gouliourisetal.,2010).ArarecaseofCandida

glabrataspondylodiscitisinanon-neutropenicdiabeticpatientisreportedherein,alongwithareviewof

theliterature.

Casereport:AcaseofC.glabrataspondylodiscitisofL3–L4metamereswasdiagnosed.Thediagnosiswas

obtainedthroughopenbiopsyofanabscessandcultureexamination.Thepatientwastreatedwith

anidulafunginandsurgicaldebridementofthelesion.

Conclusions:Thediagnosisofspondylodiscitisisoftendelayedormissed.Physiciansshouldconsiderthis

entityinthedifferentialdiagnosisoflumbarpaininordertoinitiateanappropriatetherapytoprevent

spinalcordlesionsanddisability.Thisisparticularlyrelevantinthecaseofafungalaetiology,asthereisa

recognizedglobalshifttowardsinvasivecandidiasisduetonon-albicansCandidaspecies,inparticularC.

glabrata,whichhasvariablesusceptibilitytoantifungaldrugs.

ThisisanopenaccessarticleundertheCCBY-NC-NDlicense(

http://creativecommons.org/licenses/by-nc-nd/4.0/).

Contents

Introduction ... 31

Casereport ... 32

Reviewoftheliterature ... 33

Discussionandconclusions ... 34

Conﬂictofinterest ... 34

Ethicalapproval ... 34

References ... 34

Introduction

Spondylodiscitisis aninfection of thevertebralcolumn, the incidence of which is increasing due to an increase in the

susceptible population and improved diagnostic skills. Fungal spondylodiscitis is uncommon(0.5–1.6%) and is usually due to Candida albicans (Gouliouris et al., 2010; Berbari et al., 2015). Candida glabrata, formerly known as Torulopsis glabrata, is a common saprophyte in the gastrointestinal, genitourinary, and respiratorytractsandanopportunisticpathogenoflowvirulence (Berkowitz et al., 1979). There has been a recent signiﬁcant increaseininfectionscausedbyC.glabrataduetotheincreasein theimmunocompromisedpopulation(Seravallietal.,2003).

* Correspondingauthorat:ExperimentalandClinicalMedicineDepartement, DivisionofInternalMedicine,AOUCareggi,LargoBrambilla3,50134,Florence,Italy.

E-mailaddress:manfredi.gagliano@unﬁ.it(M.Gagliano).

https://doi.org/10.1016/j.ijid.2018.01.003

1201-9712/©2018TheAuthors.PublishedbyElsevierLtdonbehalfofInternationalSocietyforInfectiousDiseases.ThisisanopenaccessarticleundertheCCBY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/).

ContentslistsavailableatScienceDirect

International

Journal

of

Infectious

Diseases

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Risk factors for candidaemia are present in the majority of patients with fungal infections and include prior use of broad-spectrumantibiotics,centralvenousaccessdevices, immu-nosuppression, neutropenia, chronic granulomatous disease, andintravenousdruguse(Gouliourisetal.,2010;Berbarietal., 2015).

The case presented herein represents the ﬁfteenth case of spondylodiscitisduetoC.glabratareportedintheliteratureand theﬁrsttreatedwithanidulafungin.Datareportedintheliterature concerningthediagnosisandtreatmentofC.glabrata spondylo-discitisarediscussedandthisnewlyreportedcaseiscomparedto previouslyreportedcases.

Casereport

A66-year-oldmalewasadmittedtothewardforlumbarpain, progressivedifﬁcultyinwalking, andimmobilizationduringthe previous2months.Hehadahistoryofdiabetes,spondyloarthrosis, hepatitisCvirus(HCV)infectionwithliversclerosis,depression, andsegmentalileitis,andhewas overweight(90kg,bodymass index(BMI)28kg/m2_)._He_had_already_been_evaluated_for_lumbar

painintheemergencydepartment,wherehehadundergonespine radiographythathadnotshownanyevidenceofpathology.During the following month, the pain had worsened and had not respondedtonon-steroidalanti-inﬂammatory drugsor opiates. Thepatientwasthereforeinvestigatedwithacomputed tomogra-phy (CT) scan of the spine, which showed signs of lumbar spondyloarthrosisandsuspected spondylodiscitisofL4. Hewas ﬁnallyadmittedtotheward.

Physicalexaminationshowedfever(37.5C),signiﬁcant func-tionalspinelimitationformobility,andweaknessofthemusclesof thelegs.Abloodtestrevealeda normalwhitebloodcell(WBC)

count, normochromic normocytic anaemia, and an increased erythrocytesedimentationrate(ESR;46mm/h)andprocalcitonin (12.69ng/ml), while C-reactive protein (CRP) was within the normalrange.QuantiferonandserologyforBrucella,Echinococcus, andTreponemapallidumwerenegative.Bloodculturesyieldedno pathogensandelectrophoresisofserumproteinsdidnotshowany monoclonal component. Electromyography (EMG) showed a sensitiveandmotorneuropathyoftheL3–S1ﬁbres.Itwasdecided toperformaspinemagneticresonanceimaging(MRI)scan,which showedhypointensityinT1sequencesandhyperintensityinT2 andSTIRsequencesattheL3–L4vertebralbodies,signsofoedema ofthedisc.Postgadoliniumimagesdetectedalesionsuspiciousof anabscess(Figure1).

Basedonthelaboratoryﬁndings,theepidemiologicaldata,and the aetiology of spondylodiscitis, the patient was started on a broad-spectrum antibiotic therapy; however, there was no improvement in his symptoms or the functional impairment. Thecasewasthendiscussedwithneurosurgeons,andasurgical exploration revealed a spinal abscess, which was treated with debridementand stabilizationofthevertebrae involved.Biopsy specimensweresentforaerobic,anaerobic,fungal,and mycobac-terial culture and yielded C. glabrata. Antifungal susceptibility testingindicatedthattheisolatewassusceptibletocaspofungin, anidulafungin (both minimuminhibitory concentrations (MICs) were0.06

m

g/ml),andmicafungin(MIC0.016

m

g/ml),accordingto ClinicalandLaboratoryStandardsInstitute(CLSI)guidelines.The patientwasevaluatedbyaninfectiousdiseasesspecialistandwas startedontreatmentwithanidulafungin200mgontheﬁrstday, followed by 100mg daily thereafter. Within a few weeks, a progressiveimprovement in thelumbar pain, resolution of the fever, and a decrease in ESR were seen, and he was ﬁnally mobilized.

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Reviewoftheliterature

AMEDLINEsearchcombiningthekeywords“Candidaglabrata”, “Torulopsisglabrata”,“vertebralosteomyelitis”,“spinal osteomye-litis”,and“spondylodiscitis”wasperformedandthereferencelists ofidentiﬁedarticleswerereviewedtoﬁndadditionalcases.Forall reported cases, special attention was paid to risk factors,

localization,methodsofdiagnosis,treatment,andoutcome.This is currentlythemostcompletereviewonC. glabrata spondylo-discitis(Table1).

Fromthedata inthe literature,themeanageof patientsat diagnosiswas61.5years(range43–74years).Eightcasesinvolved malepatientsandsevencasesinvolvedfemalepatients(53.3%vs. 46.7%).Themostprevalentriskfactorswereprioruseofantibiotics

Table1

ReviewofCandidaglabrataspondylodiscitis. Author Age(years)and

sex

Riskfactors Localization Diagnosis Medicaltherapy Surgery Outcome

ThurstonandGillespie (1981) 60M Diabetesmellitus Broad-spectrum antibiotics Obstructiveuropathy Candiduria

L4–L5 Openbiopsy AmphotericinB 5-Fluorocytosine

– Cured

Brunsetal.(1986) 63F Broad-spectrum antibiotics Obstructiveuropathy Candidaemia

T7–T8 Openbiopsy AmphotericinB 5-Fluorocytosine Ketoconazole

Performed Cured

MorrowandManian(1986) 49M Broad-spectrum antibiotics Alcoholabuse Funguria

T11–T12 Needle biopsy

AmphotericinB Performed Paraplegic

LiudahlandLimbird(1987) 49M Alcoholiccirrhosis Broad-spectrum antibiotics

T11–T12 Openbiopsy AmphotericinB Performed Cured

Imahorietal.(1987) 66F Broad-spectrum antibiotics Candidaemia Centralvenouscatheter

L2–L3 Needle biopsy

5-Fluorocytosine – Cured

Owenetal.(1992) 71F Diabetesmellitus Bowelresection Centralvenouscatheter Parenteralnutrition Candidaemia

T9–T10 Openbiopsy AmphotericinB Performed Cured

CurranandLenke(1996) 74F Colonresection Broad-spectrum antibiotics

Centralvenouscatheter Candidaemia T7–T8 Needle biopsy AmphotericinB Fluconazole Performed Cured

Bonomoetal.(1996) 85F Diabetesmellitus Rheumatoidarthritis MalignancyBroad spectrum antibiotics

C3–C4 Openbiopsy AmphotericinB Itraconazole

– Cured

Bonomoetal.(1996) 44F Degenerativejointdisease T3–T11 Openbiopsy AmphotericinB Performed Paraplegic

Dwyeretal.(1999) 43F Gastricbypass Centralvenouscatheter Parenteralnutrition Broad-spectrum antibiotics Fungaemia L1–L2 Needle biopsy AmphotericinB Fluconazole – Cured

Hendrickxetal.(2001) 72M Axillobifemoralbypass Broad-spectrum antibiotics

Centralvenouscatheter Parenteralnutrition L1–L2 Needle biopsy Fluconazole AmphotericinB – Died

Seravallietal.(2003) 64M Diabetesmellitus Gastricresection Spinalosteoarthritis Obstructiveuropathy L2–L3 Needle biopsy AmphotericinB Fluconazole AmphotericinBlipid complex Performed Presumed cured

DaileyandYoung(2011) 69M Candidaemia Colonresection Broad-spectrum antibiotics

Centralvenouscatheter Parenteralnutrition Alcoholabuse

L1–L2 Needle biopsy

AmphotericinB Performed Cured

Tanetal.(2014) 47M Psoriaticarthritis Immunosuppression Candidaemia L3–L4 Needle biopsy Caspofungin Posaconazole – Cured

Currentcase 66M Diabetesmellitus L3–L4 Openbiopsy Anidulafungin Performed Cured F,female;M,male.

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(66.7%),previous candidaemia (46.7%), previoussurgery (40%), centralvenouscatheter(40%),anddiabetesmellitus(33.3%).

Eightcasesinvolvedthelumbarspine,whileonecaseinvolved thecervicalspineandsixcasesinvolvedthethoracicspine.The most frequently affected metameres were L2 (33.3%) and L3 (26.6%).Themicrobiologicaldiagnosiswasobtainedafterneedle biopsyin53.3%ofcasesandbyopenbiopsyin46.7%ofcases.A needlebiopsyfailedinthedetectionofthepathogeninvolvedin threecasesandanopenbiopsywasthereforeperformed.

Treatment withamphotericinBplusanotherantifungaldrug wasusedin46.7%ofthecases.Athirdofthecasesweretreated with amphotericin B alone. The remaining 20% of cases were treatedwithasingleantifungaldrugdifferentfromamphotericin B. Sixtypercentof thepatientsunderwent spinal surgeryafter starting medicaltherapy,while 40% weretreated withmedical therapyalone.

Themajorityofcaseshadagoodoutcome:80%ofthepatients werecuredattheendoftherapy.Onepatientdiedandtwopatients hadirreversiblenervedamage.Only46.7%ofthecuredpatients underwentspinal surgery,while all ofthem weretreated with antifungals.However,theliteratureregardingthetreatmentofC. glabrataspondylodiscitisislimitedand theoutcomesmayhave beenaffectedbytheclinicalconditionofthepatientbeforesurgical treatment.Further clinical observations are needed to provide more conclusive evidence regarding the management of these conditions,inparticulartheroleofspinalsurgeryasatherapeutic optioninadditiontomedicaltherapy.

Discussionandconclusions

Thecasereportedherewasadiagnosticchallengebecauseback painisanon-speciﬁcsymptomamongadultsandC.glabrataisa veryrare causeof spondylodiscitis.The patient’s chronic ileitis probablycontributed to the spinal infection, causing a barrier leakagethatpromotedthetranslocationofthepathogenfromthe bowelintothecirculatorysystem,leadingtosecondary involve-mentofthelumbarspine.Nevertheless,furtherstudiesareneeded todeterminewhetherbowelinﬂammationcouldhavearole in determiningcandidaemia.

The suspicion of spondylodiscitis came from physical signs includingfeverandneurologicalimpairment,aswellastheincrease inESR.Furthermore,riskfactorssuchasdiabetes,spondyloarthrosis, age>60years,andmalesexwerepresent.ESRwasincreased,butas fortheanaemia,thiscouldhavebeenexplainedbythechronicileitis. TheWBCcountwaswithinthenormalrange.Ahighserumvalueof procalcitonin(PCT)wasfound.Bloodcultureshavelowsensitivity, and these were negative in the case patient. Based on the epidemiology,thePCT level,andtheﬁndingsonspineMRI, the patientwasstartedonabroad-spectrumantibiotictherapythatled tonoeffectiveimprovementinthesymptoms.

ThisexperiencesuggeststhatahighPCTlevel_–awell-known marker of bacterial infection (Pieralli et al., 2017) – does not necessarilyruleoutafungalinfectionand hastobereadinthe clinicalcontext.

According totheliterature,MRI shouldbe theﬁrst imaging modalityusedforpatientssuspectedofnativevertebral osteomy-elitis;ithasasensitivityof97%,speciﬁcityof93%,andaccuracyof 94%.Itsexcellentmorphologicalresolutionallowsearly recogni-tion of spondylitis. Affected vertebral bodies and discs reveal typicalalterationsinT1-andT2-weightedimages.

Nevertheless,MRIdoesnotclarifytheaetiologyoftheillness, which is crucial for initiating the appropriate therapy. A microbiological diagnosis should be established before any treatment. Biopsies (either open or percutaneous) are often reservedforpatientswithnegativebloodculturesandtheyoften establishthemicrobiologicalandpathologicaldiagnosis.

As reported in the literature, microbiological positivity is signiﬁcantly higher when surgical sampling is provided, even through minimally invasive techniques. A CT- or MRI-guided aspirationbiopsyshouldbetheﬁrstinvasivediagnosticstepinthe patient suspected of vertebral osteomyelitis. Biopsy samples shouldbesent foraerobic,anaerobic,fungal,andmycobacterial culture.However,thesensitivityofthisprocedurevariesbetween 30%and70%.Furthermore,priortreatmentmayaffecttheaccuracy ofculture(Berbarietal.,2015).

OnceneurologicalimpairmentwasprovenbyEMGandthere was no clinical improvement with antibiotic therapy, it was decidedtotakeasurgicalbiopsyoftheabscessinordertoestablish theaetiologyoftheinfection.Accordingtothisexperience,open biopsyoftheabscesswasaneffectivemethodtoobtainspecimens forcultureevaluation.Thechoicebetweenneedleandopenbiopsy wasdeterminedbytheneurologicalimpairment,whichprompted thesurgery.

Thediagnosisofspondylodiscitisisoftendelayedormissed.Itis generally misdiagnosed and mismanaged as a degenerative process (Berbariet al., 2015).Although spondylodiscitis is rare among adults, it should not be overlooked in patients with symptomaticbackpainnotrespondingtopainkillers,especiallyin patientswithriskfactors.

Spondylodiscitishasapoorprognosisintermsofmortalityand morbidity. There is a recognized global shift towards invasive candidiasisdue tonon-albicansCandidaspecies, inparticularC. glabrata, which has variable susceptibility to antifungal drugs (Andesetal.,2012)andahighermortalityrate(Fideletal.,1999). The2016recommendationsoftheInfectiousDiseasesSocietyof America for the management of Candida osteomyelitis favour initialtherapywithﬂuconazole(6mg/kgdailyfor6–12months)or anechinocandin(e.g.,anidulafungin100mgdaily)foratleast2 weeksfollowedbyﬂuconazole(6mg/kgdailyfor6–12months) (Pappasetal.,2016).However,therearealsoreportsofresistance of C. glabrata to azoles, caspofungin, and amphotericin B (Thompsonetal.,2008;Owenetal.,1992).

Surgicaldebridementisrecommendedinselectedcases,with thegoal ofdebulking theinfected tissue, securinganadequate bloodsupplyfortissuehealing,andmaintainingorrestoringspinal stability.Indicationsforsurgerymayincludethedevelopmentof neurologicaldeﬁcitsorsymptomsofspinalcordcompressionand evidence of progression or recurrence despite appropriate antimicrobialtherapy,instability,largeepiduralabscess, intracta-blebackpain,orfailureofmedicaltreatment(Berbarietal.,2015). The patient presented herein was the ﬁrst with C. glabrata spondylodiscitis tobe treated with anidulafungin.In this case, surgicaldebridementandanidulafunginwerefoundtobeeffective inthetreatmentofC.glabrataspondylodiscitis.Thisexperience couldbeusefulinthecaseofC.glabratainfectionswithevidenceof resistancetoazolesoramphotericinB.

Conﬂictofinterest

Allauthorsdenyany_ﬁnancialorpersonal relationshipswith other people or organizations that could inappropriately have inﬂuenced(biased)thework.

Ethicalapproval

Noapprovalwasrequired.Allauthorscompliedwiththeethics andpolicyofthejournal.

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