Cerebral Rhizomucor Infection Treated by Posaconazole Delayed Release Tablets in an Allogeneic Stem Cell Transplant Recipient 12 3 4 5 Q1 6 7 Q2 8 9 10 11 12 Q4 13 14 15 16 17 18 19 20 21 22 23 24 25[.]
Trang 11 Case Report
5 Q1Diego O Andreya,* , Laurent Kaisera, Stephan Emoneta, Veronique Erardb,
10
11 1 Introduction
12 Q4 Rhizomucor is an emerging fungal pathogen in allogeneic
13 hematopoieticstemcelltransplant(allo-HSCT)recipients
belong-14 ingtothegroupof Zygomycetes.1 Itsincidenceis rising in the
15 contextofwidevoriconazoleuse.CerebralRhizomucorinfectionis
16 associated with especially high mortality and treatment must
17 combineaggressivesurgicaldebridement,antifungaltherapyand
18 restoration ofimmune function wheneverpossible.2–4 Recently
19 posaconazole delayed-release tablets, registered for antifungal
20 prophylaxis,haveallowedyieldinghigherplasmalevelsthanthe
21 conventionalposaconazoleoralsolution.5–7Neverthelesstherole
22 of posaconazole new formulations remains to be defined in
23 therapeuticindications.Herewedescribethecaseofa cerebral
24 Rhizomucor infection successfully treated by posaconazole
25 delayed-releasetabletsinanallo-HSCTrecipient
26
2 Casereport
27
A30-year-oldBrazilianwomendiagnosedwithacute
myelo-28 monocyticleukemiaunderwentcytarabine-basedchemotherapy
29
At admission she presented with several pulmonary nodular
30 lesions on CT-scan, suggestive of fungal origin The initial
31 treatment consisted in empirical voriconazole (Vfend1, Pfizer)
32
200mgevery12hoursi.v.duringthreeweeks.Duetoradiological
33 progressiondespiteantifungaltherapysheunderwentasurgical
34 resection consisting in a right inferior lobectomy and wedge
35 resections of two left superior lobe nodules Microbiological
36 analysisofthenodulesrevealedpositivedirect examinationfor
37 mycelium elements identified as Rhizomucor pusillus by 18S
38 panfungalqPCRfollowedbysequence-basedidentification
(Gen-39 BankaccessionnumberHQ845298.1),whereascultureremained
40 negative Liposomal amphotericin-B (AmBisome1, Gilead
41 Sciences)at5mg/kg/dayfollowedbyposaconazoleoral
suspen-42 sion(Noxafil1,MSD)400mgevery6hours,wereadministeredfor
43 sixmonthsandsubsequentlystoppedduetoremission
44 Nineteenmonthsaftertheinitialdiagnosisleukemiarelapsed
45 and the patient underwent FLAG (fludarabine, idarubicine,
46 cytarabine, granulocyte colony stimulating factor (G-CSF))
che-47 motherapy.Atadmissionanewpulmonaryexcavatedlesionwas
International Journal of Infectious Diseases xxx (2016) xxx–xxx
Keywords:
Zygomycosis
Mucormycosis
Mucormycosis(zygomycosis)isanemergingfungaldiseaseinallogeneichematopoieticstemcell transplant (allo-HSCT) recipients A 30-year-old woman diagnosed with acutemyelomonocytic leukemiaand needingallo-HSCT presentedpulmonary andcerebralinfectionduetoRhizomucor pusillus.Thisfungalinfectionwastreatedwithsurgicaltreatmentandposaconazoledelayed-release tablets This strategy allowed reaching high drug levels that could not be obtained with the posaconazolesolution
ß2016TheAuthor(s).PublishedbyElsevierLtdonbehalfofInternationalSocietyforInfectiousDiseases ThisisanopenaccessarticleundertheCCBY-NC-NDlicense(
http://creativecommons.org/licenses/by-nc-nd/4.0/)
Q3
ContentslistsavailableatScienceDirect
j o urn a l hom e pa ge : ww w e l s e v i e r c om/ l o ca t e / i j i d
http://dx.doi.org/10.1016/j.ijid.2016.12.014
Trang 248 seen in the left superior lobe (at the sites of prior wedge
49 resections).Aleftsuperiorlobectomywasperformed.Pathological
50 and microbiological examinations, as well as panfungal PCR
51 (fungal inter spacer region (ITS) conventional PCR) remained
52 negative.8 Suspecting a relapse of the Rhizomucor infection,
53 liposomal amphotericin-B was restarted at 5mg/kg/day The
54 patientremainedinaplasia,and allogeneichematopoieticstem
55 celltransplantation(allo-HSCT)wasconsideredtheonlylifesaving
56 option In the pre-transplantation workup performed under
57 meropenem and liposomal amphotericin-B treatment, three
58 cerebralnoduleswerefoundintherightmiddletemporalgyrus,
59 therightfrontalinferiorgyrusandtherightfrontalinferiorgyrus
60 oncerebralMRI,motivatingadditionofposaconazolesuspension
61 CSFculturesandpanfungalPCR,bloodcultures,aswellasblood
62 galactomannanes remained negative After two inconclusive
63 cerebral biopsy attempts, a surgical resection of the most
64 peripheral cerebral nodule was performed Direct examination
65 (fungifluor) was positive for mycelium elements, with large
66 septationsandabsenceofbranches,(seeFig.1 confirmingthe
67 suspicionofacerebralRhizomucorinfection,probablysecondaryto
68 ahematogeneousdisseminationfromthelungduringtheinitial
69 episode,containedduringtheremissionperiod,andsubsequently
70 relapsingduringaplasia.Liposomalamphotericin-Bwasincreased
71 to 10mg/kg/day and oral posaconazole was switched from
72 solution800mg/daytodelayed-releasetablets300mg/day,due
73 tolow plasmaposaconazole(0.22mg/L).On thesameday
allo-74 HSCT(HLAhaplo-identical,donatedfromhersister,nonTdepleted
75 with myeloablative conditioning regimen including
cyclophos-76 phamide,fludarabineandi.v.busulfanandtheuseofhighdoses
77 cyclophosphamidepost-transplantationasgraft-versushost
pro-78 phylaxis)wasperformed.Duetolowposaconazoleplasmablood
79 levels (0.45mg/L), the dosing was increased to 400mg/day,
80 allowingtherapeuticlevelstobereached
81 Three weeks after resection of the cerebral fungal abscess
82 liposomalamphotericin-Bwas taperedto5mg/kg,followed by
83 3mg/kg, and finally discontinued after a total of two months
84 Posaconazoledelayedreleasetabletswerecontinuedwithplasma
85 druglevelssuperiorto2mg/L.Afterfourmonths,hematological
86 recoverywascompleteandthecerebrallesionshaddisappeared
87 onMRI,allowingreductionto300mg/day.Sixmonthspost
allo-88 HSCT, the patient was considered in remission from the
89 mucormycosis Unfortunately the patient died due toARDS in
90 thesettingofCMVpneumoniaandpulmonaryGVHD
91
3 Discussion
92
In hematological malignancies and bone marrow transplant
93 patients,lungandrhino-cerebral arethemostcommonsites of
94 Rhizomucorinfection.CNSabscessesinfectionsarenotrare;ina
95 largepublishedseriesofmucormycosis(zygomycosis),283cases
96 involved the brain.2 These infections are severe, of rising
97 importance and incidence probably in the context of wide
98 voriconazoleusefor both treatment ofinvasiveaspergillosis or
99 for secondaryprophylaxis.Cerebralmucormycosis isassociated
100 withahighmortalityrateof50%.3
101 Cerebralfungalinfections, andespecially cerebral
mucormy-102 cosis,remaindifficulttotreatbecauseofthepoorCNSpenetration
103
of most antifungals, as wellas theabsence of activity against
104 Zygomycetesof mostantifungals,includingfluconazole,
vorico-105 nazoleandechinocandins.Cureisrarelyachievedwithoutsurgical
106 removal
107 Itraconazole, posaconazole and the newly FDA-approved
108 isavuconazole have activity against Zygomycetes In salvage
109 therapies, posaconazole, which has moderate CNS penetration
110 appearedasacornerstonefortreatmentof(cerebral)
mucormy-111 cosis with a response rate of >60%.9–12 Although no exact
112 therapeuticguidelinesexist forcerebral mucormycosis,
posaco-113 nazolesolutionisrecommendedforsalvagetherapyataposology
114
of800mg/dayinadditiontohighdoseliposomal
amphotericin-115
B.13Howeverachievingadequateposaconazoleserumlevelshas
116 beenchallengingwiththeoralsolution.Inthis setting,
posaco-117 nazole delayed-released tablets, achieving higher serum levels
118 thantheoralsolutionareapromisingoption
119 HerewedescribeacaseofacerebralRhizomucorinfectioninan
120 allo-HSCT recipient treated successfully with an antifungal
121 regimen containing posaconazole delayed-release tablets and
122 liposomal amphotericin B, combined to surgery It is to our
123 knowledge the first description of such therapeutic option in
124 cerebral mucormycosis Posaconazole delayed-release tablets
125 allowed to reach therapeutic drug levels > 2mg/L that could
126 notbeobtainedwiththestandardsolution
127 Fewinformationareavailableforposaconazoledelayed-release
128 tablets,PhaseIstudiesshowed>97%reachingtherapeuticlevels
129 with300mgoncedailyinPK/PDstudies.14,15
130
No published clinical trials are available on efficacy of
131 posaconazoledelayed-releasetabletsinthepreventionofIFIsin
132 immunocompromised patients,althoughit seemsprobablethat
133 achievinghigherbloodposaconazolelevelwillconferatleastas
134 good protection against IFI than the suspension The place of
135 posaconazoledelayedtabletsforIFItreatmentneedstobedefined
136
asnoclinicaltrialsareavailable.Sofarthereisonlyasinglereport
137
onacaseofa65-year-oldmanwithanAspergillusbrainabscess,
138 treatedwithsurgicalresectionandvoriconazoleforoneyear,and
139 subsequentlytreatedwithposaconazoledelayed-releasetabletsat
140
300mg/dayefficientlyandsafely.16
141 Our observation suggests that posaconazole delayed-release
142 tabletsareaninterestingtherapeuticoptionforcerebral
mucor-143 mycosis,duetothehigherdruglevelsobtained.Thesemighteven
144
beincreasedwiththemorerecentlyFDA-approvedintravenous
145 posaconazoleformulation.Clinicaltrialswiththesenew
posaco-146 nazole formulations are needed and will hopefully show an
147 increaseofsuccessfulresponsetotreatmentandsurvival
148 Acknowledgments
149
We thank Dr Arnaud Riat from The HUG Microbiology
150 Laboratoryforprovidingthepicture
151 Fundings:Thisresearchdidnotreceiveanyspecificgrantfrom
152 funding agencies in the public, commercial, or not-for-profit
153 sectors
2
Trang 3154 Authorcontributions:DOADraftingarticle;LK,SE,VE,YC,CVD:
155 Criticalrevisionofarticle
156 Conflictsofinterest:None
157 References
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