Liposomal amphotericin B(AmBisomeÒ)efficacy in confirmed invasive aspergillosis and otherfilamentous fungal infections in immunocompromid hosts:a pooled analysis
C.Cordonnier,1M.Bresnik2and R.Ebrahimi2
1Service d’He´matologie Clinique,Hoˆpital Henri Mondor,Creteil,France and2Gilead Sciences,Foster City,CA,USA
Summary A pooled efficacy analysis applying current diagnostic standards for ca lection was
performed on previously published trials of liposomal amphotericin B for invasive
filamentous fungal infections(IFFI).Favourable respons were obrved in51%of
microbiologically confirmed cas of proven or probable IFFI.Despite the limitations
inherent in a retrospective analysis of pooled studies,the respon rates obrved in this
analysis were consistent with previous reports for antifungal therapy with
abandoningamphotericin B deoxycholate or voriconazole in the treatment of invasive aspergillosis. Key words:AmB
isome,amphotericin B,aspergillosis.
Introduction
Invasive aspergillosis(IA)and other invasivefilamen-tous fungal infections(IFFI)continue to be associated with significant morbidity and mortality,particularly in immunocompromid patients.Efficacy and survival rates for antifungal therapies for the treatment of IFFI have varied considerably depending on the patient population underlying dia,allogeneic stem cell transplantation(SCT),prence and verity of neutropenia,and receipt of immunosuppressive therap-ies].The liposomal formulation of amphotericin B(L-AMB)exhibits a broad spectrum of activity against yeast and moulds comparable with amphotericin B deoxych-olate1but with a more favourable safety profile that significantly reduces do-limiting toxicities associated with amphotericin B deoxycholate.2,3The efficacy and safety of L-AMB have been reported in a number of randomid comparative trials,3,4as well as in open-label trials and retrospective analys.5–9Subquent to the publication of the studies,diagnostic criteria for defining and classifying proven and probable cas of IFFI in immunocompromid patients for inclusion in antifungal efficacy trials have been made uniform.10To further define the efficacy of L-AMB in the treatment of IA and other IFFI for patients treated in clinical trials before2002,a pooled analysis of four prospective, clinical trial
s was performed,applying the currently accepted diagnostic standards for ca lection and efficacy analys.
Materials and methods
Patient population
Original ca report forms(CRF)for patients treated with1–15mg kg)1day)1L-AMB[AmBisome;Gilead Sciences,Inc.,Foster City,CA(formerly Nexstar)and Fujisawa Healthcare,Inc.,Deerfield,IL,USA]collected from four clinical studies were reviewed individually. The CRF were obtained from three published,prospect-ive,multicentre clinical trials.3–5The studies included: L-AMB5mg kg)1day)1vs.amphotericin B deoxycho-late for the treatment of documented and suspected neutropenia-associated invasive fungal infections,3 L-AMB1mg kg)1day)1vs.L-AMB4mg kg)1day)1 for the treatment of IA4and a safety,tolerance and pharmacokinetic trial of high-do L-AMB(7.5–15mg kg)1day)1).5The fourth study was a compas-sionate-u,multicentre study,from which cas have been previously reported in four publications.6–9
Correspondence:Catherine Cordonnier,Service d’He´matologie Clinique,
testmode
Hoˆpital Henri Mondor,51Avenue du Marechal de Lattre de Tassigny,Creteil
Cedex94010,France.
Tel.:+33(0)149812059.Fax:+33(0)149812067.
E-mail:carlcord@club-internet.fr
Accepted for publication27December2006
Original article
Journal CompilationÓ2007Blackwell Publishing Ltd•Mycos(2007),50,205–209
Methodology and analysis
The diagnosis of proven or probable IFFI was deter-mined using criteria defined by the European Organisa-tion for Rearch and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Dias Mycos Study Group(EORTC/MSG).10Cas were confirmed by histopathology or were microbiologically confirmed by culture or Aspergillus antigen.This was required so as to increa the level of certainty of IFFI and to avoid the inclusion of misleading cas only documented through halo sig
n or air-crescent sign).Chest computerid tomography scan abnormalities were assumed to be non-halo infiinor EORTC/ MSG criterion)unless otherwi stated.Additional clinical signs and symptoms of infections reported in the CRF were required to fulfil clinical criterion for IFFI. All cas with the protocol-defined IFFI that met EORTC/MSG criteria for proven or probable IFFI and in which greater than or equal to one do of L-AMB was administered were included in the pooled analysis.A favourable plete or partial respon) was bad on the investigator-determined asssments, in which criteria for complete and partial respons were previously defined per each protocol.3–9Death or discontinuation from the study before respon asss-ment could be made was considered a failure of therapy for this analysis.Survival was determined from the last follow-up visit reported in the CRF.
Results
Patients
A total of212cas were screened,of which69(33%) cas met the EORTC/MSG criteria for proven(n¼20) or probable(n¼49)IFFI.The proven and probable cas were identified infive of26cas reported in Leenders et al.[3],25of115cas reported in Ellis et al.
[4],21of44cas reported in Walsh et al.[5]and18of 27cas reported in the compassionate-u trial.6–9 Rejected cas included137cas that lacked a micro-biologically documented fungal pathogen and six cas that lacked appropriate host factors,including malig-nancy,organ transplant or infection with human immunodeficiency virus.Of the69confirmed proven or probable cas,microbiologic data ud to confirm the diagnosis of IFFI included positive culture(n¼59), positive Aspergillus antigen assay(n¼3)and histopa-thology(n¼13).Six cas had both a positive culture and documented histopathology.The most common fungal isolate identified was Aspergillus species(n¼61), with six Zygomycetes and four Fusarium isolates were also documented.
The majority of patients(n¼61;88%)had haema-tological dias,with38patients diagnod with acute leukaemia.Of the61patients,30%(n¼18) had received an allogeneic SCT.Eight of the69patients had undergone a solid organ transplant,had a solid tumour or were infected with human immunodeficiency virus.There were51(74%)males included in the analysis,and the median age of the patient population was43years(range,14–72years).The median L-AMB do administered was4mg kg)1day)1(range,1–15mg kg)1day)1),with48cas treated with L-AMB 1–5mg kg)1day)1and21cas treated with L-AMB 7.5–15mg kg)1day)1.L-AMB was administered as thefirst-line therapy in44patients and as the cond-line therapy in25patients(20becau of failure of the first-
line treatment andfive becau of amphotericin B-induced nephrotoxicity).None of the patients treated with L-AMB as the cond-line therapy had received voriconazole or an echinocandin before entry into the trials.
学汽车美容Respon
A favourable respon(complete respon,n¼15; partial respon,n¼20)with L-AM
B was obrved in 35of69(51%)cas:11of20(55%)cas of proven IFFI and24of49(49%)cas of probable IFFI(Table1). Treatment with L-AMB as thefirst-line therapy showed a higher favourable respon(61%)compared with the administration of the cond-line therapy(32%).In addition,patients with vere neutropenia(absolute neutrophil count<500cells mm)3)at baline showed a respon similar to that of patients without vere neutropenia,with16of34(47%)patients and19of35 (54%)patients achieving a favourable respon respect-ively(Table1).In patients with haematological dia, a favourable respon was obrved in31of61(51%) patients(Table1).Of the61patients,eight of18 (44%)who received allogeneic SCT and four of ven (57%)who received autologous SCT showed a favour-able respon with L-AMB.
Favourable respon rates varied by the site of infection,ranging from44%(21of48cas)for pulmona
ry infections,64%(ven of11cas)for sinus/nasal infections,57%(four of ven cas)for disminated infections and one of one ca each for subcutaneous abscess,pericarditis,and mastoiditis (Table1).Favourable respon rates by pathogen indi-cated that L-AMB was effective against Aspergillus,
C.Cordonnier et al.
Journal CompilationÓ2007Blackwell Publishing Ltd•Mycos(2007),50,205–209
Zygomycetes and Fusarium pathogens.A favourable respon was obrved in28of59(47%)patients with IA,five of six(83%)patients with zygomycosis and two of four patients with fusariosis.There were no apparent trends in respon rates bad upon the do of L-AMB received(Table2).
Survival
Of the69patients with probable or proven IFFI,35 (51%)patients treated with L-AMB survived to the last follow-up visit.Three of the patients who survived were from the clinical trial reported by Leenders et al.[3],15 patients were from Ellis et al.[4],nine patients were from Walsh et al.[5],and eight patients were from the compassionate-u trial.6–9Of the surviving patients, 23of35patients
had survival documented to ‡12weeks after the initiation of treatment.For the remaining12patients who last study visit was <12weeks following the initiation of L-AMB treatment, the mean follow-up time was65days(range,31–82days).
Discussion
The connsus guidelines defining the criteria for the diagnosis of invasive fungal infections10were developed to standardi the inclusion of patients in clinical trials. Cas of IFFI reported from studies before the latest standardisation of the diagnostic criteria by EORTC/ MSG are difficult to asss becau of the inclusion of ÔsuspectedÕorÔprobableÕcas that lacked microbiologic confirmation of a fungal pathogen.Many of the cas were presumed to be aspergillosis bad on fevers unresponsive to broad-spectrum antibacterial therapy, new and/or persisting pulmonary infiltrates and lack of isolation of specific pathogens.The would be charac-terid as possible cas by the current EORTC/MSG definitions.Furthermore,this has made it difficult to compare more recently conducted antifungal clinical studies to historic controls.Applying the newer diagnostic standards for identifying proven or probable IFFI to previously reported cas treated with L-AMB demonstrated a favourable respon rate(complete or partial respon)of51%in a population of69verely immunocompromid patients with microbiologically confirmed IFFI.Becau of the sm
all number of patients treated at each do level(1–15mg kg)1day)1)and the different protocols followed,we cannot draw any conclusions on the do-related efficacy of L-AMB in proven or probable infections.However,the data help reaffirm the efficacy of L-AMB,using currently accepted standards for documenting IFFI.Additionally,the respon rates are consistent with the results that were recently reported in a prospective,randomid trial of two do regimens of L-AMB(3mg kg)1day)1vs. 10mg kg)1day)1)in confirmed mould infections(Am-BiLoad trial).In this study,favourable respon rates were found in50%and46%of patients in the standard-and high-do groups respectively.11
Applying the newer diagnostic standards also allowed for more preci determination of IA cas and for consideration of the efficacy results in the context of prospective studies recently reported.12,13
Table1Respon rates according to prentation,treatment
indication,underlying dia and site of infection.
Overall respon,n/n(%)1
Total352/69(51;95%CI39–63)
arthritis
Diagnosis category
Proven11/20(55)
Probable24/49(49)
Treatment indication
First-line therapy27/44(61)
Second-line therapy8/25(32)
英文在线翻译成中文
After failure offirst-line treatment6/20(30)
Becau of nephrotoxicity2/5(40)
Neutropenia at baline
ANC<500cells mm)316/34(47)
ANC‡500cells mm)319/35(54)
Status of underlying haematological dia3
Uncontrolled419/40(48)
Controlled412/21(57)
Underlying dia
Haematological dia31/61(51)
Acute leukaemia25/38(66)
Chronic myeloproliferative disorders1/4(25)
Lymphoproliferative disorders3/8(38)
Aplastic anaemia1/5(20)
Myeloma1/6(17)
Allogeneic stem cell transplantation8/18(44)
Solid organ transplant0/3(0)
Solid tumour2/2(100)
HIV infection2/3(67)
Site
Pulmonary21/48(44)
Sinus/nasal7/11(64)
Disminated4/7(57)
Other53/3(100)
ANC,absolute neutrophil count;HIV,human immunodeficiency
virus.
1Complete or partial respon.
2Complete respon¼15;partial respon¼20.
manly
3Eight patients had non-haematological conditions.
4Uncontrolled dia¼evidence of active dia prent at study
entry.
5One site each of subcutaneous abscess,pericardium or mastoid
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Liposomal amphotericin B efficacy Journal CompilationÓ2007Blackwell Publishing Ltd•Mycos(2007),50,205–209
In an open-label,non-comparative trial of116patients with acute IA,13a complete or partial respon was reported in35of60(58%)patients treated with voriconazole as afirst-line therapy and21of56 (38%)patients treated with voriconazole as a cond-line therapy[6mg kg)1bid for2days,3mg kg)1IV twice daily(bid)for6–27days followed by oral 200mg day)1for up to24weeks].
In the larger,randomid comparative trial of IA published by Herbrecht et al.[12],patients were treated with voriconazole(6mg kg)1IV bid on day1;4mg kg)1 bid for‡7days followed by oral voriconazole200mg bid) (n¼144)or with amphotericin B deoxycholate1.0–1.5mg kg)1day)1(n¼133).A complete or partial respon was obrved in32%and53%of patients treated with amphotericin B deoxycholate and voricon-azole respectively.Approximately one-third of the cas were included bad on clinical and imaging criteria but without histologic or microbiologic confirmation of aspergillosis.For the cas that lacked microbiological confirmation,higher respon rates were en for both the voriconazole and amphotericin B deoxycholate groups(67.4%and42.9%respectively).This could reprent a more favourable treatment effect associated with earlier intervention and/or lower fungal burdens. Recently,an open-label study of caspofungin as the cond-line therapy was reported for83patients with proven or probable aspergillosis.14An overall(complete or partial)respon was reported in45%of the83 patients.However,the overall respon rate was only 14%in21allogeneic SCT recipients and26%in19 neutropenic patients.In the current analysis,an overall respon was reported in32%of25patients treated with L-AMB as the cond-line therapy.
In the current pooled analysis,the underlying con-ditions resulting in immunosuppression were gener
ally similar to tho in the previously reported trials.12,13For example,in Herbrecht et al.[12]and Denning et al.[13]the number of patients who had undergone allogeneic SCT(20–26%),had acute leukaemia(35–45%),had solid organ transplantation(3–6%)or were infected with human immunodeficiency virus(4–5%)was gen-erally similar to the numbers in the current study.In addition,34(49%)patients were neutropenic at ba-line in the current analysis,similar to that reported (45%)in the randomid study comparing voriconazole with amphotericin B deoxycholate12and substantially higher than the24%reported in the non-comparative trial of voriconazole.13Bad on the patient populations and similar diagnostic criteria applied to document IFFI, the clinical respon rate in this pooled analysis for L-AMB(51%)in proven or probable infection was higher than that reported for amphotericin B deoxych-olate(32%)and within the range of clinical respon reported for voriconazole(48–53%)in the treatment of IA.It is important to note that L-AMB is active against Zygomycetes infections;however,voriconazole and caspofungin are not active against this family of organisms.Zygomycetes infections may be difficult to distinguish from Aspergillus infections clinically or via imaging;therefore,this limitation with voriconazole should be taken into consideration when treating patients with IFFI if microbiological confirmation of the fungal pathogen is lacking.
In the current study,survival to the last follow-up visit in patients with proven or probable IFFI was51%, with66%of the patients surviving for‡12weeks. Becau this analysis was a retrospective ca review of patients from multiple clinical trials that followed different protocols,it is difficult to draw further conclu-sions from the survival data or compare the favourable results in this analysis to other more recently published trials.However,it is encouraging that more than half of the cas of proven or probable IFFI in a population of verely immunocompromid patients survived to the last follow-up visit.
Table2Respon rates according to do
and regimen.
Do
(mg kg)1day)1)Patients(n)Overall respon,
n/n(%)1Respon by do regimen
1169/16(56)Standard do(1–5mg kg)1day)1)
26/48(54%)
2105/10(50)
342/4(50)
41327/13(54)
553/5(60)
7.542/4(50)High do(>5mg kg)1day)1)
9/21(43%)
1052/5(40)
12.553/5(60)
1572/7(29)
1Complete or partial respon.
2Median.
C.Cordonnier et al.japanegirlswet 16
Journal CompilationÓ2007Blackwell Publishing Ltd•Mycos(2007),50,205–209
In conclusion,L-AMB has documented efficacy in the treatment of proven or probable IFFI in cas meeting current diagnostic criteria.Data from this retrospective analysis suggest an overall respon rate(51%)that is comparable with voriconazole and higher than that of amphotericin B deoxycholate;however,the obrva-tions have not been confirmed in randomid compa-rator trials.Furthermore,conclusions drawn from this study are limited in that it was a pooled analysis of lected studies that differed in drug dosage and diagnostic criteria.Despite the limitations,mounting evidence supports the role of AmBisome as an effective antifungal therapy.
Acknowledgments
This work was supported by Gilead Sciences.
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早上好韩语
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Liposomal amphotericin B efficacy
Journal CompilationÓ2007Blackwell Publishing Ltd•Mycos(2007),50,205–209
