Revue publiée : Brunet K, Rammaert B. Mucormycosis treatment: Recommendations, latest advances, and perspectives. J Mycol Med. 20 juin 2020;101007 (1).
Résumé en français :
Les mucormycoses sont des infections fongiques graves affectant les patients immunodéprimés et diabétiques. Malgré le traitement, la mortalité due à ces infections reste élevée. Cette revue présente les dernières avancées sur la prise en charge des mucormycoses. Les dernières recommandations préconisent fortement l’utilisation d’amphotéricine B liposomale en première intention, associée à la chirurgie lorsque cela est possible. L’isavuconazole et la forme intraveineuse ou à libération retardée du posaconazole sont quant à elles positionnées en seconde ligne. Plusieurs molécules sont actuellement en développement pour lutter contre ces infections fongiques invasives mais peu ont démontré leur efficacité. Malgré une efficacité in vitro, les associations de traitements antifongiques n’ont quant à elles pas montré de supériorité vis-à-vis de la monothérapie. Enfin, l’intérêt des thérapies adjuvantes est particulièrement complexe à démontrer en l’absence d’études prospectives randomisées, complexes à mettre en place devant la faible incidence et la forte mortalité des mucormycoses. Les perspectives sont cependant encourageantes. De nouvelles approches utilisant la relation champignon-hôte-antifongique ou le développement de nouvelles voies d’administration des antifongiques, comme les aérosols, pourraient en effet améliorer le traitement.
Generalreview
Mucormycosis treatment: Recommendations, latest advances, and
perspectives
K.Bruneta,b,c,*,B.Rammaerta,b,d
aINSERMU1070,Poitiers,France
bFaculte´ deme´decineetpharmacie,universite´ dePoitiers,Poitiers,France
c
Servicedemycologie-parasitologie,de´partementdesagentsinfectieux,CHUdePoitiers,Poitiers,France
d
Servicedemaladiesinfectieusesettropicales,CHUdePoitiers,Poitiers,France
1. Introduction
Mucormycosis are life-threatening invasive fungal diseases (IFD)duetofungibelongingtoMucoralesorder[1].Mucormycosis lead tomany clinical manifestations,ranging fromlocalized to disseminatedinfection.Pulmonaryordisseminateddiseasesare commonlyfoundinimmunosuppressedpatients (hematological malignancy, hematopoietic stem cell transplantation), rhino-orbito-cerebral form in diabeticpatients, and cutaneous forms inpatientshavingtrauma[2].Otherlocalizations(gastrointestinal, endocarditis,osteoarticularorisolatedcerebralinfections)areless frequent.Treatmentisbasedonsurgerywhenpossible,correction of underlying factors, and aggressive antifungal drug therapy [3]. In contrast to other fungi, few molecules are active. Amphotericin B (AmB), posaconazole (PSZ), and isavuconazole (ISZ)haveshowninvitroefficacywhilevoriconazole(VCZ)and echinocandins are inefficient [4,5]. The reference method for antifungal susceptibility testing (AST) is broth microdilution
method withthe methodologyof the European Committee for AntimicrobialSusceptibilityTesting(EUCAST)[6] ortheClinical and LaboratoryStandardsInstitute(CLSI) [7].However, amajor concern withAST is the lack of clinical breakpoints. Prognosis remainspoor,mortalityrangingfrom32to70%,andislinkedto underlyingdiseasesandclinicalforms[2].Therapeutic improve-mentisthereforemandatory[8].Theaimofthisreviewistofocus on latest recommendations, advances and perspectives on mucormycosistreatment.
2. Recentandnewantifungaldrugs 2.1. Currentrecommendations
The European Conference on Infections in Leukemia (ECIL) publishedmucormycosistreatmentguidelinesin2017[9]andthe EuropeanConfederationofMedicalMycology(ECMM)providedan updatein2019[10].Bothsocietiesstronglyrecommendliposomal AmphotericinB(L-AmB)for first-linetreatment in adults(A II) (Table1).Anotherlipidformulation,AmphotericinBlipidcomplex (ABLC)couldbeusedinmucormycosisbutwithoutcentralnervous system (CNS) involvement according tothe ECIL(B II) [9]. For JournaldeMycologieMe´dicale30(2020)101007
ARTICLE INFO Articlehistory:
Received13January2020 Accepted15June2020 Availableonline20June2020 Keywords: Mucorales Antifungaldrugs Nebulization Polyenes Azoles Prophylaxis ABSTRACT
Mucormycosisarelife-threateningfungalinfectionsespeciallyaffectingimmunocompromisedordiabetic patients.Despitetreatment,mortalityremainshigh(from32to70%accordingtoorganinvolvement).This review provides an update on mucormycosis management. The latest recommendations strongly recommendasfirst-linetherapytheuseofliposomalamphotericinB(5mg/kg)combinedwithsurgery wheneverpossible.Isavuconazoleandintravenousordelayed-releasetabletformsofposaconazolehave remainedsecond-line.Manymoleculesarecurrentlyindevelopmenttofightagainstinvasivefungal diseasesbutfewhavedemonstratedefficacyagainstMucorales.Despiteinvitroefficacy,combinationsof treatmenthavefailedtodemonstratesuperiorityversusmonotherapy.Adjuvanttherapiesareparticularly complextoevaluatewithoutprospectiverandomizedcontrolledstudies,whicharecomplextoperform duetolowincidencerateandhighmortalityofmucormycosis.Perspectivesarenonethelessencouraging. Newapproachesassessingrelationshipsbetweenhost,fungi,andantifungaldrugs,andnewroutesof administrationsuchasaerosolscouldimprovemucormycosistreatment.
C 2020ElsevierMassonSAS.Allrightsreserved.
* Correspondingauthorat:INSERMU1070,poˆlebiologiesante´,UFRdeme´decine etpharmacie,universite´ depoitiers,1,rueGeorges-Bonnet,86022Poitierscedex, France.
E-mailaddress:kevin.brunet@univ-poitiers.fr(K.Brunet).
Availableonlineat
ScienceDirect
www.sciencedirect.com
https://doi.org/10.1016/j.mycmed.2020.101007
neonatesandpediatricpopulation,L-AmBandABLCwerestrongly recommendedasfirst-linetreatment(AII)[10].
OneissuetobeaddressedisthedoseregimenofL-AmB.The ECMMrecommends5–10mg/kgand10mg/kgintheeventofCNS involvement[10].In aprospective pilotstudy(Ambizygo),high dosesofL-AmBweretestedasfirst-linetreatmentof mucormy-cosis [11]. Response rate was 43% (12/28) in patients who received7.5mg/kg/day during the first week compared with 0%(0/5)inpatientswhodidnot.AhighdoseofL-AmB(10mg/kg), combinedwithsurgeryin71%ofcases,ledtoanoverallresponse rateof36%atweek4and45%atweek12.Comparedtoanother study using L-AmB5mg/kg in mucormycosis treatment, re-sponsewassimilaratweek4(36%vs40%)butwasbetteratweek 12(45%vs35%)[12].Mortalityrateswereequivalentatweek12 (38% vs 42%). A major side effect with L-AmB high dose was creatinineleveldoublingin40%ofpatients.
TheECMMrecommendeddoseshouldnotbeslowlyincreased overseveraldaysbutafulldosemustbegivenfromthefirstdayof dailytreatment[10].
ISZ peros(PO)orintravenous(IV),PSZ delayed-release(DR) tablets or IV forms have been recommended with moderate strength (B II) and PSZ oral suspension have been marginally recommended(CII)[10].Moreover,theECMMstrongly discour-agedtheuseofAmBdeoxycholate(AmBd)(DII).
Treatmentshouldbestartedassoonaspossible,asdelayedAmB therapyislinkedtoincreasedmortality[13].Moreover,itmustbe continued until complete response on imaging and permanent reversalofimmunosuppression[10].Treatmentdurationnecessary totreatmucormycosisisunknownandfurtherstudiesareneeded tobetterdetermineit.Tofacilitatetreatmentinstabledisease,ISZ POorPSZDRtablets arestronglyrecommended.Timebetween inductionphasewithAmBandintroductionofazolesdependson clinicalandimagingresponses.Someauthorsrecommendatleast 3weeksofinductionwithparenteralAmB[14].
The ECMM has addressed recommendations concerning prophylaxis(Table2).InneutropenicorGvHD,PSZDRtabletsor IV form are moderately supported (B II, B III) and PSZ oral suspensionmarginallyrecommended(CII)whileISZismarginally supported in neutropenicpatients (CII). Finally, in solid organ transplant(SOT) recipients, PSZ and ISZ aremarginally recom-mendedinprophylaxis(CIII,CII).
2.2. Recentdrugs
ISZ, a newazole,was approvedin theUnited States and in Europein2015forthetreatmentofmucormycosis[3,15].ISZis available in oral and IV formulations, and presents some advantages:linearpharmacokinetics,fewinteractionswith cyto-chromeP450isoenzymesleadingtofewdrug–druginteractions, QTdecrease,no nephrotoxiccyclodextrin intheIV formulation (differentfromposaconazoleIVform),noneedfordoseadjustment in kidney or liver failure and in obesity, and excellent oral bioavailabilitywithno food requirements[3].AlthoughISZ has shown higher minimal inhibitory concentrations (MIC) than posaconazole [16], it is demonstrably as effective as AmB to decreasefungalburdenandtoimprovesurvivalinaneutropenic mousemodelofmucormycosis[17].ISZwastestedinVITALstudy, a phase 3, single-arm, open-label,non-comparative study.This study assessed safety and efficacy of ISZ in the treatment of mucormycosis[18].Case-control analysiswithhistoric controls treated with AmB included in the Fungiscope registry showed similarsurvivalbenefit.However,somebiasesarenoticeable.A totalof21patientstreatedwithISZwerecomparedto33matched controlswhohadreceivedAmB.AmBwasadministeredthrough AmBdformulationin7controls.Thisformulationisappreciably lessefficientthantheliposomalone.Otherdrawbackscouldbe
emphasizedintheuseofISZ.BreakthroughMucoralesinfectionsin patients receivingISZ havebeenreported[19].Moreover,some authorshave shownin Drosophila modelof mucormycosisthat preexposuretoISZenhancesthevirulenceofMucorales[20,21].In a large study including 147 patients, ISZ prophylaxiswas less effectivethanVCZorPSZagainstIFD.Twopatientswhoreceived ISZ as prophylaxispresented mucormycosis [22]. Although ISZ seemstobelesshepatotoxicthanothermould-activeazolesand present a bettertolerance profile than L-AmB [23], the ECMM recommendsonlymoderatelyISZasfirst-linetreatment[10].
Regardingcentralnervoussystem(CNS)infections,treatmentis basedonL-AmBduetoclinicalexperienceandinvitrodata[24].It hasbeendemonstratedthatISZpenetratestheblood-brainbarrier inanimal models[25],whileAmB displayslimited penetration. ConcentrationofISZ inthenecrotic centerofbrainabscesshas beenshownlow,butconcentrationininflammatorybraintissue surroundingthe abscesswasadequate, equivalenttopredicted plasmaconcentration[26].Arecentretrospectivestudyhasshown thatISZiseffectiveinMucoralesCNSinfections[27].Thisresulthas tobeconfirmedwithlargerstudies.
IVandDRtabletsofPSZwererecentlydevelopedandleadto better bioavailability and drug exposure than previous oral solution[28–30].Thisincreaseddrugexposurehasbeenrelated toincreasedPSZefficiency[31].Moreover,DRtabletsleadtoless variabilityinabsorptionandcomparedtooralsuspensionarenot affectedbyfood[32].Duetohigherserumlevel,suspensionDR tablets and IV forms are moderately recommended while oral suspensionisonlymarginallyrecommendedbytheECMMas first-linetreatment[10].Thereisnosafetyconcerncomparedtooral suspensionforthetwo newforms,sincethereis nocorrelation between serum level and safety [29–32]. However, IV form is solubilizedincyclodextrinandmayleadtorenalissues[31].Ina matched-paired analysisofpatientstreatedfor invasive mucor-mycosis,newformulationsofPSZwereevaluated[33].Theauthors showedthatPSZnewformulationsareaseffectiveasAmBas first-linetreatmentandasoralsuspensioninsalvagetherapy.However, theseresultsshouldbeinterpretedwithcaution.Numerousbiases can be noted such as small sample size, retrospective design, heterogeneityofinfectioussites,lackofdrugmonitoring,and pre-exposuretootherantifungaldrugs.
Routine therapeutic drug monitoring (TDM) is strongly recommended for patients treated by PSZ [10]. Serum trough PSZ concentrations of 1mg/L or higher are recommended. However, there is currently no conclusive evidence for routine TDMwith ISZ. Itcouldbe useful in case of suspectedtoxicity, treatmentfailure,druginteractions,obesity,orafteraswitchfrom IVtoPOtherapy[10].
2.3. Newdrugs
Some new antifungal drugs are under clinical evaluation includeRezafungin,SCY-078,orolofim,andencochleated ampho-tericinB[34].Rezafungin,anewechinocandinhasnotbeentested against Mucorales. SCY-078, member of a newglucan synthase inhibitor subclass is poorly or not active against Mucorales [35].Olorofimisamemberoftheorotomides,anewantifungal class inhibiting dihydroorotate dehydrogenase (DHODH), a key enzymeinpyrimidinebiosynthesis.Itisalsopoorlyactiveagainst Mucorales [36]. Encochleated amphotericin B is a new oral formulation of amphotericin B [34]. It has been shown to be well-tolerated,andiscurrentlytestedforcryptococcosistreatment indevelopingcountries(clinicaltrialNCT04031833).Nostudieson Mucoralesefficacyareavailable.
OtherantifungaldrugswithactivityagainstMucoralesarebeing developed.VT-1161isanovelinhibitorofthefungalCYP51within vitro activity against Mucorales. VT-1161 used as curative or K.Brunet,B.Rammaert/JournaldeMycologieMe´dicale30(2020)101007
prophylactictreatmenthasprolongedsurvivalofneutropenicmice inRhizopusarrhizusmodels[37,38].SCH42427abroad-spectrum triazolewasfoundtobeeffectiveinamurinemodel[39].APX001A (Fosmanogepix)(formerlyE1210)isanantifungalagenttargeting proteinGwt1.Gwt1isasurfaceproteinofthe glycosylphospho-tidyl inositolpost-translationalmodificationpathway. Although MICs against Mucorales are high [40,41], several authors have shownthatAPX001AisaseffectiveasAmBtoprotectmiceina R. delamar model [3,42]. Finally, PC1244 a new long-acting fungicidalazole,hasshownantifungalactivityagainstMucorales withMICsfrom0.25to2mg/L [43]but hasnotbeentested in vivo.Amongantibiotics,colistinhaspresentedmodestinvitroand invivoactivityagainstMucorales[44].
2.4. Newtherapeuticapproaches
Newapproacheshaverecentlyemergedregardingrelationship betweenfungus,antifungalagent,andhost[45].Forexample,some authorshaveemphasizedthecapacityofPSZtoaccumulatewithin leukocytemembraneduetoitslipophilicproperties.Cellsfrom HL-60 leukemiacellline differentiatedtoneutrophil-likephenotype have been loaded with PSZ and usedin an aspergillosismouse modeltodeliverPSZdirectlytotheinfectioussite[46].However, this new approach has not been tested in a Mucorales model. Bioengineering has made great improvement, especially in genetically modified cytotoxic T-cells. These modified cells can specificallytargetbeta-glucanoffunguscellwall[47].However, thisapproachhasonlybeentestedinanaspergillosismodel.
Recently, a MucoralespeptidenamedCotH3 was foundtobe linked to mucormycosis endothelial invasion by binding the endothelial cell receptor GRP78. Authors generated antibodies against CotH3 to prevent endothelial invasion. Anti-CotH3 anti-bodiesprotectedneutropenicanddiabeticmicefrommucormycosis and acted synergistically with antifungal drugs [48]. Moreover, other authors haveshownthat blockingGRP78 cell receptor by GRP78-specific immune serum mayprotectsdiabetic mice from mucormycosis[49].Thispeptide-receptorinteractionmaybeanew therapeuticwayofresearch.
2.5. Newconceptsmayguideantifungalprophylaxis
Several authors have hypothesized that Mucorales, such as Histoplasma sp. or Cryptococcus sp., can remain latent in immunocompetent patients and lead toactive diseasewhen a patientbecomesimmunosuppressed[50,51].Authorshaveshown that Mucorales spores might remain dormant in cutaneous granulomatous lesions in an immunocompetent rabbit model [52]andinsideinnategranulomainaZebrafishmodel[51].Inthe eventofimmunodepression,sporeswerereactivated.Inamurine model of latentmucormycosis,L-AmB waseffective toprevent reactivation inLichtheimiacorymbiferacolonizedmice[53].This conceptmustbeverifiedinhumantoevaluateifdecolonizationof Table1
RecommendationsfortreatmentofinvasivemucormycosisfromEuropeanConferenceonInfectionsinLeukemia6(ECIL-6)(2017)andEuropeanConfederationofMedical Mycology(ECMM)(2019),adaptedfrom[9,10].
ECIL-62017 Grade ECMM2019 Grade
First-lineantifungaltherapy
LiposomalamphotericinB 5mg/kg BII 5–10mg/kg
ForCNSinvolvement:10mg/kg
AII AIII AmphotericinBlipidcomplex WithoutCNSinvolvement BII AnywithoutCNSinvolvement
SOT:10mg/kg
BII AIII
AmphotericinBdeoxycholate CII DII
Posaconazole CIII DRtabletorIV:300mgb.i.d,day1;300mg/d
fromday2
Oralsuspension(4200mgor2400mg)
BII CII
Isavuconazole 200mgt.i.d,day1–2;200mg/dfromday3 BII
Combinationtherapy CIII LiposomalamphotericinB+caspofunginand/or
posaconazole
CII-CIII Controlofunderlyingconditions
Diabetes Controlofdiabetes AII ControlofhyperglycaemiaandKetoacidosis AIII
Immuno-suppression Discontinuation/taperingof steroids,reductionof immunosuppressivetherapy
AII Rapidlytaperglucocorticosteroiddoseto
discontinue,iffeasible,orreducedosetominimum required
AII
Surgery
Rhino-orbito-cerebralinfection AII Repeatedsurgeryinadditiontoantifungal treatment
AII Softtissueinfection AII
Localizedpulmonarylesion BIII Disseminatedinfection CIII
SOT:solidorgantransplantation;CNS:centralnervoussystem;DR:delayed-release;IV:intravenous;b.i.d:twiceaday;t.i.d:threetimesaday.
Table2
ProphylaxisrecommendationfromEuropeanConfederationofMedicalMycology (ECMM)(2019),adaptedfrom[10].
ECMM2019 Grade
Primary
Neutropenic,GvHD
PosaconazoleDRtablet(300mgb.i.dday1,300mg/dfrom day2)
BII PosaconazoleIV(300mgb.i.dday1,300mg/dfromday2) BIII Posaconazoleoralsuspension(200mgt.i.d) CII Neutropenic
IsavuconazolePOorIV(200mgt.i.dday1–2,200mg/dfrom day3;or200mg/dfromday1)
CII SOT
IsavuconazolePO/IV(200mgt.i.dday1–2,200mg/dfrom day3;or200mg/dfromday1)
CII PosaconazoleIV(300mgb.i.dday1,300mg/dfromday2) CIII Posaconazoleoralsuspension(200mgt.i.d) CIII Allinductionchemotherapy
LiposomalamphotericinB DI
NeutropenicorGvHD
Fluconazole,itraconazole,voriconazole DII
Secondary
Lasteffectivedruginthesamepatient AIII
SOT:solidorgantransplantation.DR:delayed-release.IV:intravenous.PO:peros. GvHD:graftversushostdisease.d:day.b.i.d:twiceaday.t.i.d:threetimesaday.
patients before immunosuppression could reduce the risk of reactivation.
3. Combinations
Combination are not currently recommended for first-line therapyduetolackofevidenceoftheirefficacy(CII,CIII)(Table1) [54].Theycouldnonethelessrepresentamajorwayofincreasing antifungaltreatmentefficacy[55].
Combinationsofantifungalagentshavebeenlargelytestedin vitro.Mostcombinationswereindifferent,exceptforAmB+ cas-pofungin(CAS),PSZ+CASandISZ+CAS,whichweresynergistic [55–57].Forazoles+echinocandins,fewinvivostudieshavebeen performed, showing lack of synergy [58,59]. Among AmB+ e-chinocandins,moredataareavailableinvivo.Invitrodatahave beenconfirmedinaketoacidoticmousemodelwhereL-AmBand echinocandins (micafunginand anidulafungin) appeared syner-gistic[60].CombinationofL-AmBand echinocandinsprolonged survivalanddecreasedfungalburdenofmiceinanIVmodelof R.arrhizusinfection.ThesedatawereconfirmedwithABLC+ cas-pofunginin a ketoacidotic mouse model withimprovement of survivalbutwithoutfungalclearanceinorgans[61].Casereports of combinations have been published and five retrospective clinicalstudieshavebeenperformedonantifungalcombinations. AmB+CASand/orPSZcombinationshavebeenevaluated.Fourof the five studies showed indifference [62–65] and one showed synergy [66]. However, the latter included only rhino-orbito-cerebralformsandasmallnumberofpatients.
Somenon-antifungalagentscombinedwithantifungalsdrugs haveshowninterestingsynergy.Ironchelatorshaveshownhigh synergywithantifungaldrugsinvitroandinvivo[59,67,68],but thishasnotbeenconfirmedinpatients[12].Calcineurininhibitors (cyclosporineAandtacrolimus),whichhaveimmunosuppressive effects,haveshownsynergywithAmB,PSZorISZinvitroandin vivo [69–71]. Other agents suchas MGCD290 (a Hos2 Histone DeacetylaseInhibitor),notyetFDA-approved,haveshownsynergy invitrowithPSZ[72].Althoughlovastatinhasshownsynergyin vitroand invivowithvoriconazole[73],thelatter is known to enhanceMucoralesvirulence[21].Ciprofloxacinand fluconazole haveshownsynergyinmousemodels[74],whilemiltefosineand azoles,andrifampicineandAmBhavepresentedsynergisticeffects invitro on50% [75] and 56 to 83% [76,77] of tested strains respectively.
Randomized, placebo-controlled clinical trials are needed to determinecombinationtherapyefficacy[78].Addedtoxicity,drug interactions, and cost-benefit balance of combinations remain unclear[10].
4. Adjunctivetreatment 4.1. Currentrecommendations
TheECMMand theECIL-6strongly recommendsurgeryand controlofunderlyingdiseaseincludingmanagement of ketoaci-dosis and hyperglycemia in diabetic patients, modulation of corticosteroidsand immunosuppressivedrugs,and reduction of neutropenia duration using hematopoietic growth factor if possible(AII,AII)(Table3)[9,10].Granulocytecolony-stimulating factor(GCSF)andhyperbaricoxygenaremoderately recommen-dedincaseofneutropeniaandindiabeticpatientsrespectively(B II),whileironchelatorsarestronglydiscouraged.
4.2. Surgery
Surgeryremainseasiertoperforminrhino-orbitalorcutaneous localizationsthanincerebral,pulmonaryordisseminateddisease. Surgeryisprecludedincriticalillpatients[79].Inpatientswith unifocalpulmonarymucormycosis,lobectomyorpneumonectomy haveprovidedbenefit[80].However,incaseofmultifocalorclose togreatvesselslesions,benefitislessestablishedandsurgeryis most complicated to perform. In rhino-orbito-cerebral forms, surgery is strongly linked to treatment outcome [81,82]. In a clinico-epidemiological review over 10 years, surgery was performed in 65.2% of 184 patients but only in 21.4% of hematologicalpatients[83].Surgicaldebridementincombination withmedicaltherapywasassociatedwithabetteroutcomethan medicaltherapyonly.Attentionmustbepaidtothefactthatonly retrospective studies and epidemiological data are available.