Management of cerebral azole-resistant Aspergillus fumigatus infection : a role for intraventricular liposomal-amphotericin B

Short communication

Management of cerebral azole-resistant Aspergillus fumigatus infection:

A role for intraventricular liposomal-amphotericin B

A.F.A.D. Schauwvlieghe

*, R.G.M. Bredius

, R.M. Verdijk

, F.J.W. Smiers

,

M.T. van der Beek

, B.F. Goemans

, C.M. Zwaan

, R.J. Brüggemann

, B.J.A. Rijnders

aDepartmentofInternalMedicine,SectionofInfectiousDiseases,ErasmusUniversityMedicalCenter,Rotterdam,Netherlands

bDepartmentofPaediatricImmunology,SectionofInfections,Haematology,andStemCellTransplantation,Willem-AlexanderChildren'sHospital,Leiden UniversityMedicalCenter,Leiden,Netherlands

cDepartmentofPathology,ErasmusMedicalCenter,Rotterdam,Netherlands

dDepartmentofMedicalMicrobiology,LeidenUniversityMedicalCenter,Leiden,Netherlands

eDepartmentofHaemato-oncology,PrincessMáximaCentreforPaediatricOncology,Utrecht,Netherlands

fDepartmentofPaediatricOncology/Haematology,ErasmusMC-SophiaChildren'sHospital,Rotterdam,Netherlands

gDepartmentofPharmacy,RadboudInstituteofHealthScience,RadboudUniversityMedicalCenter,Nijmegen,Netherlands

hCenterofExpertiseinMycology,Radboudumc,Nijmegen,Netherlands

ARTICLE INFO Articlehistory:

Received16December2019

Receivedinrevisedform17February2020 Accepted20March2020

Availableonline3April2020 Keywords:

Cerebralaspergillosis Azoleresistance Liposomal-amphotericinB Intraventricular Aspergillusfumigatus

ABSTRACT

Objectives:Inthepre-azoleera,centralnervoussystem(CNS)infectionswithAspergillushadadismal outcome.SurvivalimprovedwithvoriconazolebutCNSinfectionscausedbyazole-resistantAspergillus fumigatusprecludeitsuse.Intravenousliposomal-amphotericinB(L-AmB)isthepreferredtreatment optionforazole-resistantCNSinfectionsbuthassuboptimalbrainconcentrations.

Methods:Wedescribethreepatientswithbiopsy-provenCNSaspergillosiswhereintraventricularL-AmB wasaddedtosystemictherapy.Twopatientswithazole-resistantaspergillosisandonepatientwith azole-susceptibleCNSaspergillosisweretreatedwithintraventricularL-AmBatadoseof1mgweekly.

Results: We describe three patients successfully treated with a combination of intravenous and intraventricularL-AmB.Allthreepatientssurvivedbutonepatientdevelopedseriousheadaches,most likelynotrelatedtothistreatment.

Conclusions: Intraventricular L-AmB may have a role in the treatment of therapy-refractory CNS aspergillosiswhenaddedtosystemictherapy.

©2020TheAuthor(s).PublishedbyElsevierLtdonbehalfofInternationalSocietyforAntimicrobial Chemotherapy.ThisisanopenaccessarticleundertheCCBY-NC-NDlicense(http://creativecommons.

org/licenses/by-nc-nd/4.0/).

1.Introduction

Fewcasesofcentralnervoussystem(CNS)aspergillosiscaused byazole-resistantAspergillusfumigatus(ARAF)havebeenreported, andalmost allofthose reportedhada fatal outcome[1].Most patients were treated with combination antifungal therapy.

CerebralinfectionscausedbyARAFalmostalwayshaveadismal prognosis.Unfortunately, therearenoantifungalsavailable that haveactivityagainst ARAF and adequatelypenetrate thebrain.

Therefore,weaddedintraventricularliposomal-amphotericinB(L- AmB) to systemic therapy in three patients. In this study, we describethesepatientsand ourclinicalexperience. Allpatients providedinformedconsent.

2.Casepresentation 2.1.Case1

An18-year-oldwomanwithcommonacutelymphaticleukae- mia (ALL) receiving remission induction chemotherapy was diagnosed with a probable invasive pulmonary aspergillosis (IPA). Combinationtherapy withintravenous (i.v.) voriconazole andL-AmB(3mg/kgQD)wasstarted.Serumgalactomannanwas positive(OpticalDensity[OD]2.8)andsputumgrewanARAFwith

*Corresponding author at: Department of Internal Medicine, Section of Infectious Diseases, Erasmus University Medical Center, Room Na-21, P.O.

Box2040,3000CARotterdam,Netherlands.

E-mailaddress:a.schauwvlieghe@erasmusmc.nl(A.F.A.D. Schauwvlieghe).

http://dx.doi.org/10.1016/j.jgar.2020.03.016

2213-7165/©2020TheAuthor(s).PublishedbyElsevierLtdonbehalfofInternationalSocietyforAntimicrobialChemotherapy.ThisisanopenaccessarticleundertheCCBY- NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4.0/).

JournalofGlobalAntimicrobialResistance22(2020)354–357

ContentslistsavailableatScienceDirect

Journal of Global Antimicrobial Resistance

j o u r n a l h o m ep a g e: w w w . el s e v i e r . c o m / l o c at e / j g a r

theCYP51ATR₃₄/L98Hmutation.At8daysontherapy,paresisof the right arm and leg and right facial nerve paralysis were observed.BrainMRIshowedmultiplelesions(Fig.1A)andabrain biopsydemonstratedhyphaecompatiblewithAspergillus(Fig.1C).

L-AmBdosewasincreasedto10mg/kgandvoriconazole(8mg/kg BID)wasreplacedbyposaconazoleand dosedat300mg BIDto achieveserum troughconcentrations >3mg/Lwiththehopeof achieving therapeutic brain tissue levels. Posaconazole trough concentrationsof5.2and6.0mg/Lweredocumented.Follow-up MRI 15 days after the initiation of therapy showed increased perilesionaloedema.Duringthefollowing5monthsthepatient wastreatedwithoral posaconazole300mg BIDwithi.v.L-AmB daily at 5mg/kg. Six monthsafter diagnosis posaconazole was stoppedascerebrallesionsandperilesionaloedemahaddecreased andthearmandlegparesisandfacialnervepalsyhadimproved.

Chemotherapywasreinitiatedandanother3monthslaterL-AmB was discontinued. At that time the lesions on brain MRI had decreasedin sizebuthadnot disappearedcompletely. Unfortu- nately,6monthslaterthepatientwasadmittedforanepileptic seizure.MRIshowedincreaseinsizeandoedemaaroundoneofthe sevenlesions.Combination treatmentwithi.v.L-AmB(5mg/kg QD) and posaconazole (300mg BID) was reinitiated and was combinedwithintraventricularweeklyadministrationofL-AmB (1mg/week).Thepatientwasdischargedwithoutpatienttherapy withi.v.L-AmB,oralposaconazoleandonce-weeklyintraventric- ularL-AmBusinganOmmayareservoirthatwasplacedforthis purpose.TheintraventricularL-AmBtherapywaswell tolerated and continued for 4 months. The MRI remained essentially unchangedinthese4months.Thepatientwasabletowalkand cycleindependentlybuthasunilateralhandmotordysfunctionas theonlysequela.

2.2.Case2

A13-year-oldpatientwithironoverloadasaresultofmultiple transfusionsforbeta-thalassaemiawasdiagnosedwithaprobable invasivepulmonaryandmultifocalcerebralaspergillosis8months afterallogeneicstemcelltransplantation(Fig.1B).AnARAFwas culturedfrombronchoalveolarlavage(BAL)fluid.Galactomannan incerebrospinal fluid(CSF)was positive (OD 1.3).Voriconazole

(8mg/kgBIDi.v.)andL-AmB(6mg/kg)werestarted.Tendayslater anepilepticseizureoccurred.MRIshowedincreasedsizeofthe brainlesionsandagainanARAFgrewfromabrainbiopsy(Table1).

An Ommaya reservoir was placed for the intraventricular administration of L-AmBaswellas caspofungin(for detailson dosing see Table 1). Also, i.v. caspofungin (70mg QD) and flucytosine(25mg/kgQID)wereinitiated.Withthisintervention, the patient improved and lesions decreased in size. Weekly intraventricular administration of L-AmB was continued for 10 weeks and intraventricular caspofungin was continued for 6 months.Systemictherapywithflucytosine,L-AmBandcaspofun- ginwas discontinuedafter 2,6 and 6 months,respectively. No furtherimprovementoftheremainingbrainlesionswasobserved after6months.

Severalyearslaterthepatientdevelopeddisablingheadache.

On imaging the skull and dura mater diameter had thickened significantly.Adurabiopsydidnotleadtoaconclusivediagnosis.

At the last follow-up 9 years post-allogeneic transplant the complaintsof severeheadacheshad disappearedbut spasticity, occasionalepilepticseizuresandfrontallobesyndromehadledto severedisability.

2.3.Case3

A15-year-oldgirlwithcommonALLdevelopedaphasia23days afterchemotherapyinitiation.MRIshowedonelesionintheleft frontallobeandonelesioninthetemporallobe.Achestcomputed tomography (CT) showed nodular lesions. BAL sampling was performed.Galactomannan(OD4.5)was positiveandvoricona- zole-susceptible A. fumigatus was cultured (voriconazole MIC 0.5mg/L). Treatment with voriconazole (4mg/kg) and L-AmB (5mg/kg) was initiated and L-AmB stopped on day 16 when voriconazoledruglevelsweretherapeutic.Despitevoriconazole serumlevelsbetween3and12mg/L,afollow-upMRI3weeksinto therapyshowedthatlesionshadincreasedinsize.L-AmBi.v.was reinitiatedandweeklyintraventricularadministrationofL-AmB 1mgwasstartedviaaRickhamreservoirwhilevoriconazolewas continued also. Follow-up brain MRIs and lung CT at 1 and 2 monthsintothistherapyshowedadecreaseinthesizeofthebrain lesionsandnoincreaseinlunglesions.Alungbiopsyconfirmedan Fig.1.MRIshowingmultiplenodularlesions.(A)Patient1.(B)Patient2.(C)BrainbiopsyshowsseptatedhyphaewithdichotomousbranchingatsharpanglesusingaGomori methenaminesilverstain.

A.F.A.D.Schauwvliegheetal./JournalofGlobalAntimicrobialResistance22(2020)354–357 355

invasiveaspergillosis infection.Eventually,without a changein therapyallinfectionssitesimproved,aswellastheneurological disabilitiesofthepatient.After3monthsofcombinationtherapy,a step-downtovoriconazolemonotherapywas made. Duringthe following6weeksvoriconazolelevelsweresuboptimal(range0.3– 2.6mg/L)andunfortunately,6weekslater dysarthriadeveloped andanMRIshowedthatthelesionshadincreasedinsize.Abrain biopsyconfirmedtheAspergillusinfectionofthebrainandi.v.and intraventricularL-AmBwas reinitiated.Administrationof i.v.L- AmBwasstoppedafter2monthsbutintraventricularcontinued for8months,whereasvoriconazolewasswitchedtoisavuconazole forliverenzymeelevations.Eventually,follow-upimagingofthe lungsandbrainshowedagoodresponsetotherapy.Thepatientis doingwellandhasbeensuccessfullytreatedforALL.DuringALL therapy,thepatientreceivedisavuconazoleassecondaryantifun- galprophylaxis.

3.Discussion

We describe two cases of ARAF and one case with azole- susceptibleCNSaspergillosistreatedwithintraventricularL-AmB.

Brain infections with Aspergillus have a high mortality and survivors are left with at least some neurological deficit [2].

Althoughvoriconazole improved the chances of survival, ARAF nowturnsbacktheclocktotheamphotericin-Bera.

Over the last 10 years, azole resistance has become an important emerging problem and is associated withvery high mortality[3–6].Whenvoriconazoleresistanceisdocumentedina patientinfected witha cerebral Aspergillus infection, treatment becomes very difficult. Indeed, few other systemic antifungal agentshavebeenshowntopenetratethebrain.Furthermore,the therapeuticeffectofnewdrugsisstillunknown[7,8].Pharmaco- kineticandpharmacodynamicanimaldatasuggestthatcompared withotherformulationsofamphotericin-B,L-AmBresultsinthe highestbraintissueconcentrationsofamphotericin-Banditwas

effectiveastherapyinamousemodelofcandidaencephalitis[9].

Therefore,itisregardedasthepreferredsecond-linetherapyfor cerebralfungalinfectionsbutshould,atleastinitially,bedosedat 5–10mg/kg to achieve therapeutic brain tissue concentrations quickly [1,10]. For azole-resistant CNS infection, L-AmB can be combinedwithaseconddrugbutitraconazole,posaconazoleand echinocandinsdonotleadtoadequatedrugconcentrationsinCSF orbraintissuewithstandarddosingregimens[1].Furthermore,it seems that combination therapy does not lead to synergistic treatmenteffectinvitroagainstARAFisolates[11].ToimproveCSF andbrainpenetration,highersystemicexposuremaybeaimedfor tosubsequentlyreachhigherCSFandbrainconcentrationsthatcan exertapharmacologicaleffecteveninthesettingwherepathogen susceptibility is reduced. Furthermore, a damaged blood–brain barrier, which is present in patients with an angio-invasive Aspergillusinfectionwilllikelyimprovethepenetrationofselected drugs.Withthisinmind,wecombinedposaconazolewithL-AmB inthefirstcase[12].Ultimately,wedecidedtoadministerL-AmB directly into the CSF space also. The administration was well toleratedwithnosubjectivesideeffects.Contrarytothefirstand third case, weobserved long-termcomplications inthe second case.Wearguethatthesesideeffectsareprobablytheresultof chronicinflammationandscarringduringandaftertheinfection ratherthanL-AmBorcaspofungin-mediatedtoxicityalthoughwe cannotexcludewithcertaintythepossibilitythatlocalcombina- tionofdrugtherapycontributedtothesesideeffects.

Currentguidelinesdonotrecommendtheuseofintraventric- ularadministrationofantifungalsowingtotheriskofimportant adverse events (e.g. chemical meningitis and seizures) [13].

Historically,intrathecal/intraventricularadministrationofconven- tionalAmBdeoxycholatehasbeenandisstillbeingusedtotreat patientswithcoccidioidalmeningitis.Thesideeffectsofintrathe- cal/intraventricularadministrationofAmBdeoxycholatemakeit difficulttouseandonlylowdosesoftypically0.1mgareusedafter whichthedoseisslowlyincreasedupto1.0mg[14].Thereported Table1

Clinicalandepidemiologicalcharacteristicsofpatientswithcerebralazole-resistantinvasiveaspergillosis.

Factors Patient1 Patient2 Patient3

Sex,age F,18 F,16 F,15

Underlyingdisease ALL Thalassaemia,allogeneicSCT ALL

ClassificationIPA(EORTC/

MSG)

Biopsyproven Biopsyproven Biopsyproven(brainandlung)

Culturepositivesample Sputum,brainbiopsy BAL,brainbiopsy BAL

MICvoriconazole 8 16 0.5

MICposaconazole 2 0.5 0.063

MICitraconazole >16 16 0.25

MICisavuconazole – – 0.5

GMvalueblood 1.3 0.9 0.4

GMvalueCSF 0.5 1.30 0.5

GMvalueBAL 2.8 0.36 4.5

Biopsybrain Positive Positive Positive

Treatmentregimen(day afterdiagnosis)

1.Voriconazole+L-AmBi.v.(3mg/kg) (d0–d5)

2.Posaconazole+L-AmBi.v.(10mg/kg) (d5–d26)

3.Posaconazole+L-AmBi.v.(3mg/kg)+IT L-AmB^a(d26–d191)

4.L-AmB5mg/kg3/week(d191–d251) 5.Treatmentre-initiationL-AmBi.v.+IT^a (d386–d515)

1.L-Ambi.v.+voriconazole(6mg/kg)(d0–d10) 2.L-AmBi.v.+caspofungini.v.(d10–d13) 3.L-AmBi.v.+caspofungini.v./IT^b(d13–d24) 4.L-AmBi.v.andIT^a+caspofungini.v.andIT^b (d24–d32)

5.L-AmBi.v.andIT^a+caspofungini.v.and IT^b+flucytosinei.v.(d32–d97)

6.L-AmBi.v.+caspofungini.v.and IT^b+flucytosinei.v.(d97–d201)

1.Voriconazole+L-AmBi.v.(d0–d10) 2.Voriconazole(d11–d20)

3.Voriconazole+L-AmB3mg/kgi.v./weekly IT(d21–d109)

4.Voriconazole(d110–d149)

5.Voriconazole+L-AmB3mg/kgi.v./weekly IT^a(d149–d176)

6.Isavuconazole+L-AmB3mg/kgi.v.and weeklyIT(d176–d227)

7.Isavuconazole+L-AmBweeklyIT^a (d228–d348)

8.Isavuconazole(d349–XXX)

aIntraventricular/intrathecalL-AmBwasgivenatadoseof1mgweekly.

b CaspofunginIT1mgQDfor2weeks,1mg3/weekfor1monthand3/week0.5mgthereafter.ALL,acutelymphaticleukaemia;BAL,bronchoalveolarlavage;CSF, cerebrospinalfluid;EORTC/MSG,EuropeanOrganizationforResearchandTreatmentofCancer/InvasiveFungalInfectionsCooperativeGroupandtheNationalInstituteof AllergyandInfectiousDiseasesMycosesStudyGroup(EORTC/MSG)hostfactor;F,female;IPA,invasivepulmonaryaspergillosis;IT,intrathecal/intraventricular;i.v., intravenous;L-AmB,liposomalamphotericinB;MIC,minimuminhibitoryconcentration;GM,galactomannan;SCT,stemcelltransplantation.

356 A.F.A.D.Schauwvliegheetal./JournalofGlobalAntimicrobialResistance22(2020)354–357

sideeffectsofAmBdeoxycholateledustooptforintraventricular L-AmBinstead.BasedonatheoreticaltotalCSFvolumeofca.100– 150mLinourpatients,theadministrationof1mgofL-AmBwould resultinapeakCSFconcentrationofL-AmBof10

m

comparable to the peak plasma concentrations after systemic administrationbyGrolletal.[9].Distributionkineticsaswellas clearancemechanismwereunknownsowehadnoknowledgeon possibleaccumulation, hencewe startedwith a presumedsafe dose.Incase1wetriedtomeasureL-AmBinretrospectonresidual CSF fluid but no L-AmB couldbe detected (limit of detection:

0.5mg/L). Inhindsightwe arguethattheclearanceofL-AmBis muchmorerapidthaninitiallyexpected.Thisisexplainedbythe factthat500mLofCSFisproducedandreabsorbedeachdayand helpswithclearingL-AmB.Boththedoseandfrequencyofonce- weeklyintraventricularadministrationof1mgL-AmBmightthus be suboptimal and a higher dose as well as a more frequent administrationmaybepreferredforfuturepatients.Intrathecal/

intraventricularL-AmBatahigherdose(10mgperadministration) for 7 consecutive days was shown to be well tolerated in 18 patientswithcryptococcalmeningitis[15].Althoughtheexactrole of intrathecal/intraventricular L-AmB remains tobe defined in patientswithanAspergillus infectionof theCNS,weproposeto initiateintrathecal/intraventricularL-AmBassoonasvoriconazole resistanceisdocumentedatadoseof5mgandpreferablytwice weekly. If available, L-AmB CSF concentration monitoring may guidedosingafterthefirstdose.

Finally,whetherlocaltherapyneedstobegiveninconjunction withsystemictherapy is unknown.The benefitof combination therapymaybeamorefavourableratioofplasma/brainconcen- trationsandperhapsalongerdetainmentofadequateCSF/brain concentrations.

Caseserieslikeourshaveseverallimitations.Inparticular,all three patientsreceived systemic treatmentalso. Therefore, the exactcontributionof theintraventricularL-AmBadministration cannotbedefined. However,itisveryunlikely thatprospective clinicalstudieswilleverbeperformedtofindthebestpossible treatmentoptionfor very rareinfections likeCNS aspergillosis.

Therefore,treatmentshouldbebasedoninvitroandanimaldata andeventuallytheexperiencedescribedincasereportsandcase seriescanbehelpfulaswell.

In conclusion, three patients with a CNS infection with A.

fumigatusweretreatedwithcombinationantifungaltherapythat includedintraventricularL-AmB.Allthreesurvivedbutonepatient wasleftwithseveresequelae.

Funding

Thisstudywasperformedaspartofourroutinework.

Competinginterests

A.F.A.D.SchauwvlieghehasreceivedtravelgrantsfromAbvie, Amgen,RocheandGileadtoattendinternationalconferencesnot relatedtothismanuscript.B.J.A.Rijndersreceivedresearchgrants fromGileadandMSDoutside thecontextofthis study.Healso receivedtravelgrantsfromMSD,Gilead, BMS,Jansen-Cilagand ViiVandreceivedpersonalfeesfromGilead,ViiVandGreat-Lake

pharmaceuticals. He servedas an advisorto Gilead, ViiV,BMS, Abbvie,Jansen-CilagandMSD.R.J.B.Brüggemannhasservedasa consultanttoand hasreceivedunrestrictedand researchgrants fromAstellasPharma,Inc.,F2G,GileadSciences,MerckSharpeand Dohme Corp., and Pfizer, Inc. All contracts were through RadboudumcandpaymentswereinvoicedbyRadboudumc.None ofthisworkisrelatedtothismanuscript.Allotherauthorshaveno competingintereststodeclare.

Ethicalapproval Notrequired.

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