Key words β Candida
Table1. MCFGCPAstudygroup Investigator (representative) YoshitsuguMiyazaki NaoyukiMiyashita RyoichiAmitani KenjiOgawa AtsuyukiKurashima ToshiroKiguchi MichiakiMishima YuichiInoue HiroshiSaito HiroyukiTaniguchi HirofumiMiyawaki KunihikoYoshimura AkihikoKawana YosukeAoki MasaoTateyama YoshiroMochizuki YoshihiroYamamoto TadashiIshida YoshioTaguchi TakeshiOguma HirokiTakahashi OsamuTaguchi JiroOkimoto MichiakiHoriba AkitakaIwagaki JunichiKadota KiyoyasuFukushima YasumasaDohtsu AtsushiNagai AtsuoSato TakefumiSaito KatsuhiroSuzuki YasuhiroYamazaki MasaruOritsu HidekiNishiyama ( ):CurentAfiliation Institution SecondDepartmentofInternalMedicine,NagasakiUniversityHospitalofMedicineandDentistry (DepartmentofBioactiveMolecules,NationalInstituteofInfectiousDiseases) DivisionofRespiratoryDiseases,KawasakiMedicalSchoolHospital DepartmentofPulmonaryMedicine,OsakaRedCrossHospital DepartmentofPulmonaryMedicine,NationalHospitalOrganizationHigashiNagoyaNationalHospital DepartmentofRespiratoryDiseases,NationalHospitalOrganizationTokyoNationalHospital (DepartmentofRespiratoryMedicine,Double-BaredCrossHospital) DepartmentofRespiratoryMedicine,TachikawaMedicalCenter,TachikawaGeneralHospital (DepartmentofRespiratoryMedicine,KiguchiInternalMedicineClinic) DepartmentofRespiratoryMedicine,KyotoUniversityHospital InternalMedicine,IsahayaHealthInsuranceGeneralHospital DepartmentofRespiratoryMedicine,AichiCancerCenter,AichiHospital DepartmentofRespiratoryMedicineandAlergy,ToseiGeneralHospital DepartmentofInternalMedicine,KagawaPrefecturalCentralHospital DepartmentofRespiratoryMedicine,ToranomonHospital DepartmentofRespiratoryMedicine,InternationalMedicalCenterofJapan,ToyamaHospital (SecondDepartmentofInternalMedicine,NationalDefenseMedicalColegeHospital) DepartmentofLaboratoryMedicine,SagaUniversityHospital FirstDepartmentofInternalMedicine,FacultyofMedicineandUniversityHospital,UniversityoftheRyukyus InternalMedicineDepartment,NationalHospitalOrganization,HimejiMedicalCenter DepartmentofRespiratoryMedicine,SaseboCityGeneralHospital (SecondDepartmentofInternalMedicine,NagasakiUniversityHospital) DepartmentofRespiratoryMedicine,KurashikiCentralHospital DepartmentofRespiratoryMedicine,TenriHospital DepartmentofInternalMedicine,SaitamaSocialInsuranceHospital (DepartmentofRespiratoryMedicine,KawasakiMunicipalHospital) ThirdDepartmentofInternalMedicine,SapporoMedicalUniversityHospital ThirdDepartmentofInternalMedicine,MieUniversityHospital DepartmentofRespiratoryMedicine,KawasakiHospital (CenterofRespiratoryDiseases,KawasakiMedicalSchoolKawasakiHospital) DepartmentofChestDisease,OgakiMunicipalHospital (GeneralInternalMedicine,GotoClinic) FirstDepartmentofInternalMedicine,OsakaMedicalColegeHospital (InternalMedicine,KinshukaiGroup,HanwasumiyoshiHospital) DepartmentofInternalMedicineI,OitaUniversityHospital DepartmentofInternalMedicine,NagasakiPrefectureTaramiHospital (DivisionofRespiratoryMedicine,JapaneseRedCrossNagasakiGenbakuIsahayaHospital) DepartmentofMedicine,NagasakiMunicipalHospital (DepartmentofInternalMedicine,HouseikaiHospital) DepartmentofRespiratoryMedicine,TokyoWomen'sMedicalUniversityHospital DepartmentofRespiratoryMedicine,NationalHospitalOrganizationMinami-KyotoHospital DepartmentofRespiratoryMedicine,NationalHospitalOrganizationIbarakihigashiNationalHospital DepartmentofRespiratoryMedicine,NationalHospitalOrganizationKinki-ChuoChestMedicalCenter DepartmentofRespiratoryMedicine,NationalHospitalOrganizationDohokuNationalHospital DepartmentofRespiratoryMedicine,JapaneseRedCrossMedicalCenter DepartmentofRespiratoryDiseases,JapaneseRedCrossWakayamaMedicalCenter Aspergillus Candida Aspergillus I
Aspergillus γ β β
χ II
Table2. Patientprofilesinmonotherapyversuscombinationtherapy Diagnosis Gender Age (years) Bodyweight(kg) Underlying disease * Durationof treatment (days) Meandaily micafungindose (mg) Variable/category CNPA Aspergiloma Male Female 24to64 65to79 8to9 Mean±SD Mean±SD Absent Present Mainunderlyingdisease Tuberculosissequela Non-tuberculousmycobacteriosis COPD Pneumonia(pathogenunknown) 4to14 15to28 29to84 Mean±SD <_ 15 <_ 3 Mean±SD Numberof patients n= 91(%) 57(62.6) 34(37.4) 62(68.1) 29(31.9) 31(34.1) 49(53.8) 11(12.1) 67.8±11.4 43.6±9.5 2(2.2) 89(97.8) 27(3.3) 15(16.9) 12(13.5) 12(13.5) 15(16.5) 16(17.6) 6(65.9) 42.5±24.9 58(63.7) 33(36.3) 181.±58.2 Micafungin monotherapy n= 48(%) 29(6.4) 19(39.6) 3(62.5) 18(37.5) 12(25.) 29(6.4) 7(14.6) 69.7±1.3 44.2±1.4 1(2.1) 47(97.9) 14(29.8) 1(21.3) 6(12.8) 5(1.6) 11(22.9) 14(29.2) 23(47.9) 32.6±2.7 35(72.9) 13(27.1) 169.9±55.1 Antifungal combination therapy n= 43(%) 28(65.1) 15(34.9) 32(74.4) 11(25.6) 19(44.2) 2(46.5) 4(9.3) 65.6±12.3 43.1±8.6 1(2.3) 42(97.7) 13(31.) 5(11.9) 6(14.3) 7(16.7) 4(9.3) 2(4.7) 37(86.) 53.6±24.6 23(53.5) 2(46.5) 193.3±59.6 Typeof Itraconazole 39(42.9) 39(9.7) concomitant antifungaldrug Amphotericin-B 11(12.1) 11(25.6) Imaging-based severity Severityscore Mild Moderate Severe 1to3 4to6 32(35.2) 34(37.4) 25(27.5) 66(72.5) 25(27.5) 21(43.8) 16(33.3) 11(22.9) 36(75.) 12(25.) * :Somepatientshadmorethan1underlyingdisease. :Bothitraconazoleandamphotericin-Bwereadministeredto7patients. :Totalscorecalculatedfrom imaging,age,bun,andpao2points;eachpointisdefinedasfolows: Imaging:1pointformildcases,2pointsformoderatecases,and3pointsforseverecases. Age:1pointformalesaged7yearsorolderandfemalesaged75yearsorolder. BUN:1pointforpatientswithBUNof21mg/dLormore,ordehydration. PaO2:1pointforPaO2of6mmHgorless. :Doserangeofitraconazolewas5 4mg/day.(Mean±SD:213.2±82.6mg/day) :Chi-squaretestformonotherapyvs.combinationtherapy. 11(25.6) 18(41.9) 14(32.6) 3(69.8) 13(3.2) Statistical test p=.5
Table3. Overaleficacyrateandimprovementinclinicalsymptoms/findings,imagingfindings,mycologicaleficacy,orserologicalfungal findings Al CNPA Aspergiloma Micafungin monotherapy Antifungal combination therapy Variable/category Overalclinicaleficacy Clinicalsymptoms/findings Imagingfindings Mycologicaleficacy Serologicalfungalfindings Overalclinicaleficacy Clinicalsymptoms/findings Imagingfindings Mycologicaleficacy Serologicalfungalfindings Number of patients 8 5 3 42 41 41 11 15 38 38 38 18 11 Marked improvement 2 6 * 3 1 Responders 51 31 2 24 27 Improvement 24 15 3 25 15 4 Non-responders No change 9 22 4 7 12 2 7 5 Aggravation * :Fungaleradicationornegativeconversion. :Improvementinclinicalsymptoms/findings,imagingfindings,mycologicaleficacy,orserologicalfungalfindings. 29 19 1 18 11 6 4 1 2 1 3 1 2 Overaleficacy 63.8% (51/8) 62.% (31/5) 66.7% (2/3) 57.1% (24/42) 63.4% 36.6% 54.5% 4.% 71.1% (27/38) 65.8% 39.5% 55.6% 36.4% Table4. Overaleficacybymicafunginduration Variable/category Durationof treatment (days) <_ 14 15to28 >_ 29 Alpatients (n= 8)(%) 3/9(33.3) 11/15(73.3) 37/56(66.1) Numbersinparenthesesrepresentresponse. Micafungin monotherapy (n= 42)(%) 3/7(42.9) 11/14(78.6) 1/21(47.6) Antifungalcombinationtherapy (n= 38)(%) /2(.) /1(.) 27/35(77.1) Table5. Overaleficacybyconcomitantantifungaltherapytiming Responders Non-responders Overaleficacy(%) Timingof concomitant antifungal Beforemicafunginuse (n= 2) Concurentlywithmicafunginuse (n= 4) Aftermicafunginuse (n= 14) 15 3 9 5 1 5 75. 75. 64.3 Al (n= 38) 27 11 71.1
Severityscore Variable/category Table6. Overaleficacybyseverityscore Meandailydose ofmicafungin (mg/day) Alpatients (n= 8)(%) Micafungin monotherapy (n= 42)(%) Antifungal combinationtherapy (n= 38)(%) 1to3 <_ 15 3/43(69.8) 17/26(65.4) 13/17(76.5) (mildilness) > 15 13/19(68.4) 5/7(71.4) 8/12(66.7) 4to6 <_ 15 2/7(28.6) 1/5(2.) 1/2(5.) (severeilness) > 15 6/11(54.5) 1/4(25.) 5/7(71.4) Numbersinparenthesesrepresentresponse. Micafungin monotherapy n= 61 Antifungal combination therapy n= 48 Table7. Adversedrugreactionprofile(safetyanalysisset) Typeofadversedrugreaction * Abnormalhepaticfunction (AST,ALT,γ -GTP,orBilincreased) Renalimpairment Lymphocytecountdecreased Others 1) Total Incidenceofadversedrugreactions Abnormalhepaticfunction (ALPincreased,etc.) Rash Nausea Others 2) Total Incidenceofadversedrugreactions Numberof patients 13 2 2 8 (11) 22 (35) 36.1% 5 (5) 3 (3) 2 7 (12) 14 (22) 29.2% Serious () (1) () () (1) () () () Severityofilness Moderate (8) (1) () (4) (13) () () (1) (3) Mild Numbersinparenthesesrepresentthenumberofreportedadversedrugreactions. * :Thistablelistsadversedrugreactionsin2ormorecases. :Includingsomepatientswithtwoormoreadversedrugreactions. Breakdownof1):Thefolowingeventwasobserved:thrombocytopenia,vertigo,angiopathy,rash,injection siteextravasation,oedemaperipheral,bloodpotassium increased,eosinophilcountincreased,proteintotaldecreased,plateletcountincreased,andeosinophilpercentage increased. Breakdownof2):Thefolowingeventwasobserved:pseudomembranouscolitis,hemolyticanemia,vomiting,injectionsiteerythema,injectionsitepain,injectionsitewarmth,pyrexia,bloodchloridedecreased,bloodsodium decreased,lymphocytecountdecreased,whitebloodcel countdecreased,andplateletcountincreased. (12) () (7) (21) (5) (3) (1) (8) (17) γ
Variable/category Numberofpatients(n= 19) Age (years) Table8. Profileofadversedrugreactionsbyageandmeandailymicafungindose(safetyanalysisset) 24to64 65to79 8to9 Number of patients 61 17 36 8 Micafunginmonotherapy Numberof patients withany adversedrug reaction 22 6 12 4 Incidence (%) 36.1 35.3 33.3 5. Statistical test * Number of patients 48 21 23 4 Antifungalcombinationtherapy Number ofpatients withany adversedrug reaction 14 6 8 Incidence (%) Meandailydoseof <_ 15 48 18 37.5 29 1 34.5 micafungin(mg/day) > 15 13 4 3.8 19 4 21.1 *:Cochran-Armitagetest :Chi-squaretest :Nosignificantdiference 29.2 28.6 34.8. Statistical test * III in vitro iv vivo Candida Aspergillus
in vitro in vivo γ
Aspergillus Candida albicans Aspergillus fumigatus in vitro Candida albicans Aspergillus fumigatus
Candida Aspergillus Candida Aspergillus Candida Aspergillus β Candida albicans