This article isThis article 10.1111/myc.12960doi: differences to lead between the of thisversion citethisarticle and asVersion Record.Please copyediting, paginationbeen throughthe andproofreadingtypesetting, process,may which Accepted This article acceptedhas been for publication andundergo contributedequally. authors *These Articleand the R Thompson OA Cornely Subtitle: Mycology Consortium and Research Education Infection Fungal Invasive Defining Breakthrough Article :Review Article type DR GEORGE : ID 0000 (Orcid KONTOYIANNIS DR DIMITRIOS 0000 ID: (Orcid HÖNIGL MARTIN DR ID :0000 (Orcid CORNELY A. OLIVER PROFESSOR 7) 6) 5) 4) 3) 2) 1)

Wales Health Pathology, Westmead Hospital; Centre for Infectious Diseases and and Diseases Infectious for Centre Hospital; Micr Westmead Pathology, Health South New Wales ICPMR, Services, Laboratory Microbiology and Diseases Infectious for Centre Austria Innsbruck, Innsbruck, University Medical E ECMM Microbiology, and Hygiene of Division Austria Graz, Graz, of University Medical Diseases, Infectious of Section and Pulmonology of Division USA CA, San Diego, SanDiego, ofCalifornia University ofInfectious Diseases, Division Colo University of Köln), (ZKS Centre Cologne Clinical Trials Bonn Germany Cologne, Cologne, site partner Research, Mycology, Infection Medical for for Centre Excellence of German Center ECMM Medicine, Internal of I Department Aging in Responses Germany Cologne, Cologne, of University Stress (CECAD), Cellular on Cluster Excellence Cologne European Confederation of Medical Mycology Medical of Confederation European C

( ategorizing Antifungal Therapy F Therapy Antifungal ategorizing ECMM * RICHARD THOMPSON (Orcid ID :0000 (Orcid THOMPSON RICHARD obiology, Sydney Medical School, The University of Sydney, Sydney, Australia Sydney, Sydney, of University The School, Medical Sydney obiology,

1 III ,2,3

10 protected byprotected copyright. All rightsreserved. , , M Hoenigl M for the for the )

Mycoses Study Group Education and Research Research and Education Group Mycoses Study

* 4 ,5

, C Lass C

- ( 0002 - MSG Flörl - - 6 1653 ailures ERC , S , C - 0002 ) - - -

A 0001 and the – 2824) -

Chen Position Paper ofthe Paper Position 0001 - 8051 - 9599

7 ( -

, ECMM 8518

European Confederation o Confederation European DP DP Kontoyiannis -

xcellence Center Center xcellence 2940) - 3137)

- 5750) ne fullpeer review buthasnot )

gne, Cologne, Germany gne, Cologne,

- oon (ZF, nvriy of University (DZIF), Cologne Mycoses Study Group Group Study Mycoses Consortium 8 , C for O Morrissey O - Associated Diseases Diseases Associated

Medical Mycology, Mycology, Medical f Medical f Medical

( MSG

9 , - ERC G

eorge )

This article isThis article dissemination treatment after occurs as defined initiation treatment discontinuation drug after interval dosing defining symptom or sign clinical attributable first the fungi IFI Breakthrough approval. for document theupdated andcirculated received, comments addressed The authors developed literature Medical of Confederation European the and ERC) research. establish paper position This systemic receiving B Abstract 478 Tel.: +49221 oliver.cornely@uk StrKerpener Medicine ofInternal I Department FAAM, FECMM FIDSA, FACP, MD, Cornely Oliver A. Prof. Author Corresponding refractoriness persistence, relapse, words: Key Accepted as emerged have (IFI) infections fungal invasive reakthrough Article 10) 9) 8) outside the spectrum of activity of an antifungal an of activity of spectrum the outside

Infectious Diseases, UC Diseases, Infectious of Division Medicine Internal and Immunology and Microbiology Medical of Departments Monash AlfredHealthand Diseases, Infectious Houston Center, Cancer Anderson M. D. Texas of University Health, Employee and Control, Infection Diseases, Infectious of Department

ratruh F dpns n hraoiei poete ad extends and properties pharmacokinetic on depends IFI breakthrough

Representatives of the Mycoses Study Group Education and Research Consortium (MSG Consortium Research and Education Group Study Mycoses the of Representatives for definitions applied definitions for ,

progression of disease and therefore similar to similar therefore and disease of progression and circulated circulated and . 62, 50937 Cologne, Germany Cologne, 62,50937 . ratruh ivsv fna dsae aprilss mu aspergillosis, disease, fungal invasive Breakthrough, can occur. can protected byprotected copyright. All rightsreserved. - was 8 - antifungals; koeln.de 5523

with

defined as as defined

,

n i cue b te ae ahgn t h sm st, although site, same the at pathogen same the by caused is and non ne fr a for need ongoing to all to

es however, - Davis Medical Center, Sacramento CA,USA Medical Center,Sacramento Davis

members and published published and any any , University Hospital Cologne Hospital University , ral apial dfntos f breakthrough of definitions applicable broadly

IFI occurring during exposure to an antifungal drug, including including drug, antifungal an to exposure during occurring IFI

consensus criteria for defining breakthrough IFI are are IFI breakthrough defining for criteria consensus .

Persistent IFI Persistent of of ,

mycological finding finding mycological the two organizations two the tfna therapy ntifungal through M ycology ycology

. University, Melbourne, VIC,Australia Melbourne, University,

The time of breakthrough IFI was defined as as defined was IFI breakthrough of time The

describes IFI that is unchanged is that IFI describes 2018

non

(ECMM) reviewed (ECMM) . A draft proposal f proposal draft A .

- response to treatment to response It . or radiological feature radiological or a

significant problem in patients patients in problem significant

s itnt rm ercoy IFI, refractory from distinct is for for cormycosis, treatment failure, failure, treatment cormycosis, comment and suggestions. suggestions. and comment

the or definitions was definitions or at least least at

relevant English English relevant IFI for clinical clinical for IFI . / Relapsed IFI Relapsed . The period period The . stable since since stable until

miss

one one ing. -

This article isThis article IFI of treatment failure treatment The trials clinical in outcomes treatment for (FUNDICU) definitions patients ICU for criteria consensus ( (SOT) Transplanta Lung and radiological IFI patient to is infection consensus Group challenging. diagnostic patients neutropenic factors individ therapy antifungal of initiation the to prior epidemiologic interpretation trial clinical definition criteria, consensus absence of particular of infections fungal invasive Introduction of goal ultimate the with mycology, clinical in research epidemiological T ESCMID hese

clinical trial results. trial clinical re Accepted Articlebreakthrough se quire a host risk factor for development of diseas of development for factor risk host a quire

recipients

ual host host ual definitions . These interpretations are further complicated by complicated further are interpretations These . proposed proposed dcto ad R and Education T Furthermore M ) he European Organization for Research and Treatment of Cancer and the Mycoses Study Study Mycoses the and Cancer of Treatment and Research for Organization European he , s jr imp ajor have emerged as emergedas have the European Confederation of Medical Mycology ( Mycology Medical of Confederation European the

assays definitions of of definitions regardless of of regardless s , and , defined as defined

. These differences complicate accurate comparisons between clinical between comparisons accurate complicate differences These .

protected byprotected copyright. All rightsreserved.

[16, 17] [8]

characteristics mycological findings vary vary findings mycological

F con IFI

. Currently, the European Society for Clinical Microbiology and Infectious Diseases Diseases Infectious and Microbiology Clinical for Society European the Currently, . definitions definitions of complete response and partial response to antifungal treatment, as well as as well as treatment, antifungal to response partial and response complete of [5] been have rovements nbe cmaaiiy f endpoint of comparability enabled . ,

. [4] tion

differentiating

Similarly, detection of fungal elements in elements fungal of detection , impacting clinical presentation, radiological findings and findings radiological presentation, clinical impacting , tinue their their

esearch Consortium Consortium esearch

(IFIs) proven issued IFI issued a .

significant problem in problem significant

immune status status immune are intended intended are , however pe however , o opiae niugl treatment antifungal complicate to lbrtr ad aigahc tde, and studies, radiographic and laboratory , the , probable consensus criteria consensus

differentiation breakthrough breakthrough s

and classification and a between , , hee in chieved rsistence, refractory disease, disease, refractory rsistence,

is often difficult and involves accurate interpretation of of interpretation accurate involves and difficult often is and to support the design of future clinical trials and and trials clinical future of design the support to and underlying disease, disease, underlying and (EORTC/MSG osbe F fr lncl trials clinical for IFI possible

[9] IFI from from IFI patients receiving systemic antifungal systemic receiving patients

of relapsing infection and reinfection remains remains reinfection and infection relapsing of . host group host

o hgl imncmrmsd patients immunocompromised highly for The The e for for normally the the s

(e

differences differences i n . cardiothoracic cardiothoracic s g prophylaxis, prophylaxis,

clinically clinically EORTC/MSG also proposed consensus consensus proposed also EORTC/MSG of breakthrough IFI IFI breakthrough of ., prolonged neutropenia prolonged ., - lncl ras n prophylaxis on trials clinical ERC

ECMM s

sterile body sites. sites. body sterile , )

t he International Society for Heart for Society International he have recently recently have

( un 1 Figure between neutropenic and non and neutropenic between of ) whereas and apparent

increas treatment and outcome of of outcome and treatment relapse solid organ transplantation transplantation organ solid MSG ). fungal and iatrogenic iatrogenic and fungal

probable and possible and probable [6, ing Breakthrough Breakthrough vary widely vary - , but pre but , or the development development the or ERC the the 7]

released released P . the trials and hinder hinder and trials roven IFI applies applies IFI roven n re, p brief, In

performance of of performance ). are comparability comparability Since c Since s - develop existing IFI IFI existing

[1 [11

b - updated updated 3] - etween 15] . linical

IFI I roven roven n the the n

s and and [10] ing

in in - . ,

This article isThis article document updated (MSG suggestions members and all comments to organizations both of presidents re studies the of quality the grade to intent abstrac were IFI breakthrough and IFI of definitions performed retrieved prophylaxis”, prophylaxis antifungal the engaged in council ECMM the forming nations of organization medical laboratory and mycology medical Europe Methods relapsed of definitions applicable broadly establish to is paper strategies clinical between enable of definitions

Acceptedcommendations Article

, A searched authors The the of Executives defining for criteria consensus While pdmooi studies epidemiologic and the United States. States. United the and

IFI

. were were

draft proposal for for proposal draft Based on existing IFI definitions definitions IFI existing on Based

for use in clinical useinclinical for eaaey o hematology for separately “

esset rfatr, r refractory, persistent, niugl treatment antifungal protected byprotected copyright. All rightsreserved. design reviewed for additional relevant reports. Stud reports. relevant additional for reviewed 27 studies

for defining breakthrough IFI, as well persisten well as as IFI, breakthrough defining for ainl yooia societies mycological national again

and and

n treatment and and ,

for finalapproval. for conduct of conduct MSG Te uhr addressed authors The . research

(iii) Pub definitions was developed, and was was and developed, was definitions siaig h tu burden true the estimating - MSG R ad h EM slce a selected ECMM the and ERC

guarantee guarantee e fr eeat nls language English relevant for Med

, bekhog fna infec fungal “breakthrough ”, ( -

www.ecmm.info ERC comprise ERC clinical studies on on clinical studies .

through elapsed, and and elapsed, . , intensive intensive ,

The executive committee reviewed each study and and study each reviewed committee executive The

of of mycologist fair our and other groups other and our the presence of of presence the

December December

, assessment t comprised of of comprised s ed from each relevant manuscript. manuscript. relevant each from ed

infectious d infectious breakthrough breakthrough ) car

s 1, 19] [18, all IFI

( e www.msgerc.org breakthrough, . and ,

comments comments 2018 -

. Both organizations organizations Both . R) council / ERC)

s f disease of

y selection and and selection y of antifungal drug drug antifungal of . IFI are are IFI

iseases physicians with expertise in in expertise with physicians iseases

one delegate from each of the 27 the of each from delegate one Search Search solid group tion” t

[6, 7, 9, 10] 9, 7, [6, IFI , refractor

eevd and received, - articles on on articles sent out by the respective respective the by out sent organ transplantation. transplantation. organ r ugnl needed urgently are . readily

,

of authors from from authors of term persistent, refractory, refractory, persistent, h re The (ii) ; CM s the is ECMM );

- t members (ECMM) for for (ECMM) members he goal of this position position this of goal he facilitate facilitate s y, and relapsing IFI y, andrelapsing data extraction were were extraction data available, available, included ference are and management management and clinical studies of of studies clinical collaboratively circulated circulated There was no no was There compari s

“a f article of c Australia, Australia, onsensus umbrella ntifungal ntifungal drafted drafted

to sons sons : and and The The . the the

(i) s

This article isThis article neutropenic to treatment. Empiric prophylaxis of after discontinuation until7days ofprophylaxis initiation after 7 days from leukemi myeloid acute prophylaxis antifungal of cessation neutropenia are IFI which reach vari the as begin IFI. breakthrough from IFI difficulty substantial microbiological) clinical, (host, criteria diagnostic infection breakthrough for confirmatory day the to refer disease fungal with consistent symptoms patient of day first the as infection breakthrough the how report not do prophylaxis antifungal studying trials clinical of majority The infection. breakthrough of day difficult the increasing days several over results radiographic and laboratory Importantly IFI typically agents immunosuppressive drugs antineoplastic targeted with treated when particular in IFI, acquire to risk high carry still IFI for malignanc in used Definitions literature the of Review Statements Recommendations/Position

the Accepted Article[11, 12] mii atfna teay trials therapy antifungal empiric ability day of first dose first of day ning

pharmacologic stead pharmacologic and are thus thus are and day of randomization, which frequently frequently which randomization, of day , Prophylaxis. Prophylaxis.

represents the primary primary the represents however

y of of a rfet KP cnieain o te rg studied drugs the of considerations PK/PD reflect may

, and

[22] patients who are who patients the chemo

defin protected byprotected copyright. All rightsreserved. , ,

or a or adesd hs issue this addressed y d particular in of the of

there is substantial variation substantial there is iagnosis of IFI of iagnosis

T ed therapy

In prophyla In [11, 23, 25] 23, [11, he same same he a is the elapsed antifungal exposure time that separates pre separates that time exposure antifungal elapsed the is

precise clinical trials in in trials clinical

r a receiving induction chemotherapy, chemotherapy, induction receiving a

as elatively first first

Some studies do not report report not do studies Some breakthrough

y

[20] , day , [22]

positive positive state inconsistencies duration those with those .

.

persistently febrile persistently xis xis The majority of studies reviewed studies of majority The study often requires an assessment an requires often homogeneous population homogeneous

3

. ( studies [24, 26] [24,

Table 3 Table A recent Italian consensus statement focusing on patients with with patients on focusing statement consensus Italian recent A mycological test or radio or test mycological endpoint . Empiric antifungal therapy is defined as treatment in in treatment as defined is therapy antifungal Empiric . of

hematology

or or

a

infection [24 [11 days , cute leukemia cute

it is it at ) - - 27] . 5 2, 22] 21, 15,

seen in antifungal prophylaxis prophylaxis antifungal in seen Lastly, Lastly, day 7 day ,

, in the definition of of definitionin the . take place take especially hlt others whilst i.e.

Current Current s despite broad despite for diagnosis diagnosis for

≤7 days ≤7 [27, 29] [27, . s inconsistent is definition Others . Most on th on ,

EORTC/MSG after initiation of initiation after share neutropenia as as neutropenia share important to important

prior

to study to

is 1, 25] [12, ains ih underlying with patients

defined require

aspect s describing the the describing s and correlation of patient symptoms, symptoms, patient of correlation and graphic finding consistent with IFI as as IFI with consistent finding graphic use

to the to - ,

, ≤ ,

spectrum antibacterial the antibacterial spectrum 2, 29] [28, what constitutes breakthrough breakthrough constitutes what use icuig h time the including , d Dfntos nld the include Definitions . .

15 days 15

Non [13, 15] [13,

ciia approach clinical a d definitions are used are definitions h peec of presence the breakthrough IFI IFI breakthrough

first first define breakthrough define a very early very a ( iue 2 Figure - neutropenic patients may may patients neutropenic ,

prophylaxis while others while antifungal

trials [23] y

end - in defining a precise precise a defining in the major the or ≤30 days ≤30 or existing (“baseline”) (“baseline”) existing

) are also applicable applicable also are .

Another area of of area Another time p time of the period the of

.

dose all necessary necessary all eesr to necessary Some of t of Some as occurring occurring as h

refer to refer

ematolog [30]

risk factor risk

to classify classify to oint, [23] assigning assigning

[12, 14] [12, .

IFI [21] rapy, in in rapy,

end of of end . Some Some . ,

such such

post post as and and , the the IFI his his at in ic it .

This article isThis article study drug present >10 if infection tract urinary to peritonitis intraabdominal sites body or invasion proven histologically as candidiasis invasive Prophylaxis. therapy antifungal emptive strategie antifungal early for candidiasis invasive of development the predicting in utility their determine to evaluated prospectively and developed been have systems which define to difficult therapy comorbidities paren IFI catheters, venous to central predisposing exposure, factors overlapping possess frequently patients ICU pro IFI for risk increased at them placing immunosuppression severe with consistent Definition o diagnosis of day a prophylaxis define not did patients IFI hematology breakthrough in infection fungal of treatment Targ Definitions S (e.g., IFI retrospective of markers indirect or direct via galactomannan). evidence mycological and signs radiological typical Pre day 1 onset IFI breakthrough of day the trials infection fungal for evidence mycological or signs radiologic typical of absence the Accepted Article ome - - emptive inflammatory phase, septic patients enter a period of relative of period a enter patients septic phase, inflammatory eted treatment. eted

used [34] studies studies

in [48, 49] [48,

to day 3 to day s

urinary

[62] 6, 62] [61, the the of the of

used in clinical trials clinical in used or

Randomized clinical trials evaluating fluconazole prophylaxis in ICU patients defined defined patients ICU in prophylaxis fluconazole evaluating trials clinical Randomized . treatment

fr example for , [42, 43] [42,

or day3 or introduced modifications of of modifications introduced Despite the recognition of increased risk risk increased of recognition the Despite

who protected byprotected copyright. All rightsreserved. modified EORTC/MSG 2002 definitions definitions 2002 EORTC/MSG modified In .

D 1, 44 [16, [31] day of diagnosis were not reported werenot reported diagnosis day of

specimens iagnosis driven iagnosis

were actually patients with breakthrough IFI withbreakthrough patients actually were studies

of Similarly, t Similarly, addition, - 46]

after initiation of initiation .

. specific specific Pre

oe i nt nlz sprtl toe ains h had who patients those separately analyze not did Some

followed followed [5, 56

discharge from ICU from discharge - . Observation periods periods Observation . emptive antifungal therapy is defined as treatment in patients with with patients in treatment as defined is therapy antifungal emptive ainny HIV, malignancy, s

, -

hs suis util studies these 60] he large randomized controlled clinical trials published on targeted targeted on published trials clinical controlled randomized large he and

patient

in intensive care intensive in

. and randomized controlled clinical trials clinical controlled randomized

empiric treatment empiric o truh the through /or either the either

timeframes used timeframes

groups [50 serum - a ntiin gsritsia poeue, n multiple and procedures, gastrointestinal nutrition, tal 55] .

2002 2002 Stratification of patients using these systems allows allows systems these using patients of Stratification

[61] influenza, or or influenza, may benefit from targeted prophylaxis targeted from benefit may ized a variety of other definitions ranging from from ranging definitions other of variety a ized .

galactomannan optical density density optical galactomannan

units were from randomization randomization from were

[7, 39 [7, [35

tlzto o nwr igotc tests diagnostic newer of utilization until 7 days after days until 7

- factors factors [31 to 43] . - 41, 43] 41, I - . CU 33] classify an IFI an classify ≥1

5

and the lack of of lack the and

colony forming units of of units forming colony patients frequently develop develop frequently patients

oiie utr from culture positive or or emphysema over the past few few past the over

from those with primary IFI primary with those from the

immunosuppression. immunosuppression. 2008 EORTC/MSG criteria criteria EORTC/MSG 2008 [35

cessation of cessation as - 38] breakthrough var breakthrough

, prospective , eg, r e.g., , requiring corticosteroid corticosteroid requiring uniform until day 7 day until decades, [47] index

treatment . ecent antibiotic antibiotic ecent normally

. After the initial initial the After

M definition received prior prior received Candida .

ost use [35, 39 [35, after Risk scoring scoring Risk In addition, addition, In

conditions it remains remains it

[16, 17, 44] ied of these these of for [36 -

41] end of of end

sterile sterile

[31, 34] -

8 43] 38,

were , and and , from from [6, 42] [6, s pre

for for . . - f

. .

This article isThis article IFI breakthrough non more recipients transplant liver on study endpoint further a as disease invasive of signs of absence the in colonization invasion of proof histologic to addition in anastomosis bronchial the entity separate a as tracheobronchitis board review data independent criteria fulfilled of occurrence as IFI breakthrough of diagnosis of day the of definition p regimens immunosuppressive transplantation after months Prophylaxis. immunosuppression epidemiologic by determined is risk individual The are many but group, heterogeneous Definition enrollment pathogen baseline the from different recent more studies Some infection breakthrough evaluated were candidiasis treatment Targeted day28 concluded on and treatment ofstudy first dose 2008 Pre on ended treatment and antifungal current infection with line in was candidemia and candidiasis invasive of definition treatment. Empiric Accepted rophylaxis Article - emptive criteria for the definition of breakthrough infection. The period of assessment started with the the with started assessment of period The infection. breakthrough of definition the for criteria

for proven and probable fungal infection infection fungal probable and proven for [82]

6 65] [6, s respectively , -

cutaneou up up

for

sd in used treatment Antifungal prophylaxis is prophylaxis Antifungal Te eid o te rmr edon aayi cmecd n a 1 f empi of 1 day on commenced analysis endpoint primary the for period The .

to 72 hours thereafter, and ended at ended thereafter,and hours to 72 protected byprotected copyright. All rightsreserved. other other began on the first the first began on

h fir the

Two randomized clinical trials evaluated empiric antifungal treatment antifungal empiric evaluated trials clinical randomized Two .

, Five large randomized clinical trials clinical randomized large Five sts ln wt ohrie nxlie sepsis unexplained otherwise with along sites s

often determined by the type of organ transplanted transplanted organ typeof bythe often determined clinical trials in in trials clinical SOT .

[67 The single randomized study on pre on study randomized single The . t in f infection of sign st -

71] Study definitions of breakthrough IFI followed EORTC/MSG EORTC/MSG followed IFI breakthrough of definitions Study recipients ly .

[67 In fact, o fact, In

[74] have - 71] . The course may be may course The . [75]

[83] . None reported reported None . . , day of prophylaxis of day either either

. defined probable invasive candidiasis upon colonization of 2 or or 2 of colonization upon candidiasis invasive probable defined eie bekhog infection breakthrough defined F at at [75] One study in lung transplant recipients defined defined recipients transplant lung in study One , ne study did not e not did study ne ew prospective trials have been performed performed been have trials prospective ew recommend

defined by positive culture from a tracheobronchial ulcer or or ulcer tracheobronchial a from culture positive by defined . high high organ solid

[67 The majority of published studies do studies published of majority The day 4 - 69]

risk [81] Te bevto tm fr uh finding such for time observation The .

[63]

n te a o wih l ncsay rtra were criteria necessary all which on day the and of de novo IFI, IFI, novo de of in all but one study, which used which study, one but all in

ed or

six al

transplantation dfnto o te a o danss f a of diagnosis of day the of definition a [76 on day28 on [78, 83] for lung transplant recipients for the first 3 first the for recipients transplant lung for prolonged in those receiving more aggressive aggressive more receiving those in prolonged

after

[67, 68] - exposures and the the and exposures

80] on treatment of candidemia and/or invasive invasive and/or candidemia of treatment on xplicitly define define xplicitly .

or or Two studies defined the day of diagnosis diagnosis of day the defined studies Two , - end of treatment of end

emptive treatment treatment emptive or

the day of the day

12 [64] and

[69]

post post treatment

also of also

s week follow week

(SOT) 8 79] [8, a s proven as

SOT [72, 73] breakthrough infection breakthrough

[81] .

. qualitative qualitative infection breakthrough . This study used airway airway used study This

[76, 79,[76, 81,82]

[66] O rec SOT guidelines .

The

not explicitly state a a state explicitly not . applied EORTC/MSG EORTC/MSG applied

[79] -

. up assessment

. IFI

period A retrospective retrospective A s

. pet are ipients

by a species species a by and ended at ended and net state of of state net to evaluate evaluate to

s for proven proven for

Aspergillus

consensus consensus [63, 64] [63,

ea at began defini

by an an by . The The . rical rical

[71] ng - 4 a . .

This article isThis article is treatment differentiate to requirement IFI proven or probable clinical with of improvement patients in only initiated is treatment targeted the during late or early occur whether B pathogen, host, breakthrough w trials, clinical IFI breakthrough prior in heterogeneity significant the from Resulting Definitions week whe periods, when day the as IFI breakthrough of diagnosis treatment. Targeted months thereafter months 12 to SOT from IFI probable as candidemia IFI proven for criteria sites sterile physiologically from histology or culture met were heterogeneous. methodologically Pre I breakthrough applied study The report. pathology or definitions 2008 EORTC/MSG culture positive first the of day the as IFI breakthrough treatment. Empiric studies 2

ekhog IFI reakthrough

[82] Accepted as classified Article - empti , 3 ,

[88]

[76]

did not not did post SOT post

and 3 months and treatment intention is intention treatment e treatment. ve

, 6 , 8, 86] [85, is

proposed by MSG by proposed

initiated in patients not fulfilling not patients in initiated n 7, 83] [78,

IFI

FI breakthrough IFI breakthrough reported, began on days 1 days on began reported, protected byprotected copyright. All rightsreserved. provide provide , and and

,

[84]

. and [86] ( and for for and Table Table ,

Breakthrough A . or .

iatrogeni

Studies on t on Studies prospective prospective

n dd o gv a definition a give not did one

12 months 12

[89] temporal temporal [7] , radiological radiological , 1

. These were used in another study, with the exception of classifying classifying of exception the with study, another in used were These .

) clinical after treatment. h fw tde o pre on studies few The .

[85] Causes of Causes breakthrough , and focused on the period from SOT to 3 months 3 to SOT from period the on focused and , c - .

ERC and ECMM ERC and

causes Where reported the observation period for breakthrough IFI ranged ranged IFI breakthrough for period observation the reported Where course of antifungal antifungal of course

( prophylactic, empiric, pre empiric, prophylactic,

definition Figure 1 Figure argeted argeted scenarios of treatment failure that need to be differentiated from from differentiated be to need that failure treatment of scenarios

IFI cohort study on study cohort [79] Two Two

[85]

, and for one retrospective study retrospective one for and , cus uig xoue o n niugl drug antifungal an to exposure during occurs

or mycological signs of IFI under IFI of signs mycological or , and from first dose of preemptive antifungal treatment to 6 6 to treatment antifungal preemptive of dose first from and ,

( Table Table breakthrough IFI breakthrough studies ) antifungal antifungal

. [89]

s

IF

IFI should be defined according to published consensus consensus published to according defined be should IFI [77, 80] 2 I from refractory IFI. refractory from I

diagnostic or day 6 day or

) .

defined breakthrough IFI on the day all IFI criteria criteria IFI all day the on IFI breakthrough defined . EORTC/MSG criteria criteria EORTC/MSG

various organ transplant transplant organ various

treatment [87] exposure

- [87] [88] . emptive treatment in SOT patients are are patients SOT in treatment emptive

criteria are multifa are Breakthrough IFI were defined as positive positive as defined were IFI Breakthrough wih s ls t te 02 EORTC/ 2002 the to close is which ,

of pre of - emptive or targeted or emptive

[1] in SOT recipients defined the day of of day the defined recipients SOT in for - . emptive treatment and ended one one ended and treatment emptive

In contrast In s p As

IFI, therefore development of IFI IFI of development therefore IFI, ceted r definition er met were at such treatment such , and and ,

e propose definitions for for definitions propose e 5 years post SOT post years 5 types ,

prophylaxis or empiric empiric or prophylaxis can be can ; breakthrough may may breakthrough ;

T . 8, 89] [88, post defined the day of of day the defined ,

herefore pre irrespective of of irrespective

SOT . grouped into grouped

Observation Observation - is an added added an is emptive or or emptive

to define define to

[81] ,

. initial initial

MSG T wo wo

This article isThis article treatment of beginning the thus and process, disease the of control of sign early an constitutes ( disease untreated refractory from distinct is but treatment further IFI Persistent diagnostics example for factors other and all IFI breakthrough of day the as defined be therefore breakthrough radiological of diagnosis of Day either defining periods different interval IFI breakthrough IFI an that rang evaluated study drug f period the antifungals, new in case the antifungal the by defined is exposure antifungal occur findings a Period IFI the outside pneumonia bacterial intercurrent is “possible” from differentiated patients hematology in scenario “p for required is pathogen fungal malignancies hematologic underlying with patients for (e.g., criteria breakthrough IFI breakthrough /treatment emergentIFI /treatment

Accepted necessary Article ing

relapse f

h period The or from 8 hours to 7 days, days, 7 to hours 8 from after drug discontinuation. discontinuation. drug after .

(e breakthrough Given the differences in differences the Given 14][12, in in / is is known known clinical . g criteria occurring . thus thus s n immunosuppressed an .,

This category describes IFI that that IFI describes category This protected byprotected copyright. All rightsreserved. or

. fe a iiu atfna exposure antifungal minimum a after time to steady state steady to time

new IF new if the first first the if h .

spectrum of activity of an antifungal (or placebo) placebo) (or antifungal an of activity of spectrum igh Thus, sign of of of the of

ly variable after antifungal drug discontinuation should definitely be classified as as classified be definitely should discontinuation drug antifungal after ratruh IFI breakthrough o , Is IFI

. b

breakthrough IFI breakthrough [1] . c reakthrough infection reakthrough r mycological finding finding mycological r

onsensus definitions definitions onsensus It is important to point out that p that out point to important is It .

in symptom, sign,

breakthrough IFI. breakthrough ces o mgn ad te facilities other and imaging to access , and th is oal” r poe” ae o bekhog IFI breakthrough of cases “proven” or robable” half )

(

period depends on the drug evaluated drug the on depends period Necessarily, Necessarily, Table 3 Table should not used be not should host

- IFI life and life or p

amckntc n pamcdnmc properties pharmacodynamic and harmacokinetic .

also also s ta persistent that so , breakthrough IFI breakthrough . Breakthrough IFI

) . r idn o II cus ihn es th less within occurs IFI of finding or s When the When s nhne sne ramn initiation treatment since unchanged is extends

antifungal dosing intervals, intervals, dosing antifungal

occurring occurring s is determined by the biology of the disease process disease the of biology the by determined is Detection of of Detection

trbtbe to attributable can be diagnosed diagnosed be can drugs with different dosing intervals will have have will intervals dosing different with drugs .

The time it takes takes it time The

se

beyond assuming assuming to define define to

after the period the after

IFI parameters are unknown, unknown, are parameters should commence with the first dose of of dose first the with commence should

Figure Figure re

any any

begins on the the on begins - - existing

the last dose of the antifungal antifungal the of dose last the also known as as known also f ratruh IFI breakthrough the day of day the ungal p ungal optimal direct or indirect or direct is 1 only

. IFI ). to diagnose an IFI by IFI an diagnose to also defined as as defined also Th . and and

if first signs/symptoms or or signs/symptoms first if

athogen athogen

e day of completion of of completion of day e with with of of mostly progress if left left if progress mostly

compliance unrecognized ( breakthrough IFI breakthrough which Table breakthrough IFI breakthrough the latter the day of the first first the of day stable

, which should should which , causing disease causing 3 [6] an one dosing dosing one an needs detection of a a of detection ) which may be may which breakthrough breakthrough ). A common common A ). .

We suggest suggest We .

and – M

currently currently

IFI is not is IFI

fulfill inimum inimum

disease disease

of the the of be to needs needs .

are ing

This article isThis article futurestudies literature, trial clinical of comparability Likely research th With Conclusion is syndrome immune reconstitution during infection ofthesame flare frompersistent different thus aspergillosis invasive applicable imaging results including or be utilized pathogen site same atthe pathogen same by the IFI Relapsed reconstitution orimmune ofIFI torefractoriness clinicalprogression to assign determination refractory r system temporary is that progression clinical and radiological to lead also may non clinical new or worsening IFI Refractory response of lack ofIFI. the course during immunocompetent represent could it i while and/or neutropenic persistently in response therapeutic represent success

Acceptedpossible Article - respon ,

the most important implication of of implication important most the

ese [10] ecovery in the field of clinical mycology clinical of field the in may be may . . Definition of persistent IFI may vary by patient group, e.g. e.g. group, patient by vary may IFI persistent of Definition . –

infection without without infection For proven proven infection, For s ( definitions

. iue 1 Figure e an an The term relapse describes IFI that occurs after antifungal treatment after antifungal occurs IFIthat describes relapse The term

. to antifungal treatment antifungal to protected byprotected copyright. All rightsreserved. increase of non of increase n h cnet f F, refractor IFI, of context the In

[91] difficult to determine, to determine, difficult . Immune reconstitution Immune . is sufficient ) . In clinical trials, trials, clinical In . , we intend to support the support to intend we ,

, as defined previously for e.g. chronic hepatosplenic candidiasis e.g.hepatosplenic for chronic definedpreviously as , are are signs or or signs need isolation of the causative fungal pathogen fungal causative the of isolation

or - result culture based fungal biomarkers fungal based culture

treatment refractory IFI( refractory treatment the [6] ed . Re symptoms or radiological features attributed to IFI to attributed features radiological or symptoms

same species is sufficient to fulfill the definition. For definition. tothe fulfill sufficient is same species to fill to fill s. While these definitions represent the the represent definitions these While s. lapse requires requires lapse , although d although , [90] and the .

consensus . Immune reconstitution can complicate assessment, as it it as assessment, complicate can reconstitution Immune . These important gaps important

Data Review Committees usually perform the final final the perform usually Committees Review Data

has therefore to be ruled out when defining an IFI as as IFI an defining when out ruled be to therefore has

full armamentarium of armamentarium full definitions are not meant to guide clinical practice clinical guide to meant not are definitions y disease is defined as as defined is disease y in patients who are or have become become have or are who patients in design design issemination can occur can issemination

definitions of breakthrough IFI breakthrough of definitions a response to antifungal antifungal to response of future clinical trials trials clinical future of . Figure 1 Figure

like like ).

Differentiation of relapse versus versus relapse of Differentiation g

alactomannan in cases of of cases in alactomannan essential ,

diagnostic methods should should methods diagnostic mncmrmsd hosts mmunocompromised and coinciding with immune immune with coinciding and the the

[92] same clinical picture clinicalpicture same progression of disease, disease, of progression . persistent disease may may disease persistent

The i The treatment first, and is andis first, treatment

[93] and epidemiological epidemiological and status

. [10] dentity of a of dentity

is

and is caused caused is and to increase to

as a a as f published of

probable probable and and . result of of result

–

more if

the . ,

This article isThis article final approval. for again document updated the circulated received,and comments DPK, ( hematology contributions: Author F2G, Vical. Cidara, Astellas, GRT and Dohme. COM Pharma Mayne Therapeutics, Cidara Pharma, Astellas Amplyx Pharmaceuticals, DPK SCAC Dohme. Sharp and CLF MH Pfizer Gilead, from Basilea, Astellas, honoraria receivedlecture Vical, and Tetraphase, SeresTherapeutics, Scynexis, PSI, Rempex, Pfizer, Paratek Pharmaceuticals, Octapharma, Ci Limited, UK Biosys Basilea, Astellas, Amplyx, AllecraTherapeutics, Actelion, to isaconsultant Scynexis, Pfizer, Merck/MSD, Therapeutics, Melinta MedPace, Medicines Company, Janssen Pharmaceuticals, Gilead, O of Conflicts Potential This work was Funding Acknowledgement SC Accepted Article AC received AC

received research grants from Astellas Pharma, Gilead, personal fees from Basilea, Gilead, Merck Gilead, feesfromBasilea, personal Gilead, Pharma, from Astellas research grants received

receiv received personal fees from Gilead, Merck Sharp and Dohme, United Medical, is a consultant to to isaconsultant United Medical, and Dohme, Merck Gilead,Sharp from fees personal received received research grants from Amplyx, Astellas, Cidara, F2G, Vical, is a consultant to Amplyx, to Amplyx, consultant isa F2G,Vical, Cidara, Astellas, from Amplyx, grants research received

C received research grants from Gilead, Merck Sharp and Dohme, is an advisor advisor is Dohme, an and Sharp Merck Gilead, from grants research received . received research grants from MSD Australia, personal fees from Gilea feesfrom personal Australia, MSD from grants research received ,

O C

M, and GRT and M, OM, GRT, CL GRT, OM, statement ed research grants from Gilead. from research grants ed dara, Da Volterra, F2G, Gilead, IQVIA, Matinas, MedPace, Menarini Ricerche, Merck/MSD, Ricerche, Menarini MedPace, Matinas, IQVIA, Gilead, F2G, DaVolterra, dara,

( OAC, MH), intensive care (GRT, (GRT, care intensive MH), OAC, research grants from Actelion, Amplyx, Amplyx, from Actelion, grants research supported in part by funding from the NIH ( NIH the from by part funding in supported protected byprotected copyright. All rightsreserved.

, and was circulated within the two organizations. The authors addressed any addressed authors The organizations. two the within circulated was and , F Interest , MH). , Review, s Review,

A

draft proposal for proposal draft tudy selection and data extraction were performed separately for for separately performed were extraction data and selection tudy

C OM, SC OM, definitions was developed was definitions Astellas, Basilea, Cidara, Da Volterra, F2G, F2G, Volterra, Da Cidara, Basilea, Astellas, AC , OA , MH113477 C, CL C,

F ), and ), ) .

solid d.

by

- organ transplantation transplantation organ

Merck/MSD and Merck/MSD OAC, CLF, SC CLF, OAC, to MerckSharp

AC , MH, This article isThis article 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1

Accepted Article Maertens JA, Raad II, Marr KA, et al. Isavuconazole versus voriconazole for primary primary for voriconazole versus KA, etal.Isavuconazole JA,RaadII,Marr Maertens trial. arandomized aspergillosis: forinvasive therapy antifungal Combination R, etal. Herbrecht Schlamm HT, Marr KA, transplantation. cell hematopoietic after allogeneic fungal infection ofinvasive prevention for voriconazole double Randomized, TJ,etal. SL,Walsh JR,Wingard Carter graft severe in prophylaxis for fluconazole or Posaconazole etal. DH, JH, Vesole Lipton AJ, Ullmann 318 2011;155: stem allogeneic haematopoietic following prophylaxis itracona versus etVoriconazole CC, al. Kibbler A, Marks DI,Pagliuca neutropenia. with patients in prophylaxis itraconazole or fluconazole vs. al. Posaconazole DJ,et J,Winston Maertens OA, Cornely Chemothe leukaemia. lymphoblastic in acute mycoses invasive prevent to placebo B versus amphotericin liposomal of comparison Randomized etal. J, Maertens T, OA, Leguay Cornely and Treatment Research for Organization and European Group Study Mycoses diseases: fungal invasive of trials in clinical outcomes andstudy totherapy responses etal.Defining DA, R, Stevens Segal BH,Herbrecht (FU patients inICU Definitions infections the FUNgal of units.Protocol in care intensive patients incriticallyill adult diseases M,Scu Bassetti Transplant Lung transplant recipients. incardiothoracic infections of ofdefinitions standardization Danziger ML, S,Mooney Husain consensus. international st hematopoietic and cancer with patients immunocompromised in infections fungal invasive Defining opportunistic B,et al. Pauw Rex de JH, Ascioglu S, Group. Consensus (EORTC/MSG) Group Study and Allergy Institute of National the Group and Cooperative Infections Fungal ofCancer/Invasive and Treatment forResearch Organization the European from fungaldisease ofinvasive definitions Revised al. JP,et TJ, Donnelly Walsh B, De Pauw Mycoses Aspergillus versus Assay Flow Non in Aspergillosis Invasive JD, Jenks malignancies. hematologic with patients count of the leukocyte and condition the underlying both on should depend aspergillosis A R,Sulahian A,Porcher Bergeron A 5 agents: spectrum antifungal ofbroad introduction the after candidemia Breakthrough et JF, al. FF,Meis Tuon GL,Breda isavuco receiving patients CR,DiPipp Rausch 30. Directions. and Future Patient: Concepts Current Hematology Br DP. Kontoyiannis Lewis RE, MS, Lionakis (SECURE): a phase 3,randomised aphase (SECURE): i of treatment

protected byprotected copyright. All rightsreserved.

201 Mehta SR, Taplitz Taplitz R, Mehta SR, r

2017;72: 2359 2017;72: - versus 9; nvasive mould disease caused by Aspergillus and other filamentous fungi fungi filamentous other and byAspergillus caused disease mould nvasive - 27. deller L, Giacobbe DR, et al. Developing definitions for invasive fungal fungal forinvasive definitions etal.Developing DR, Giacobbe L, deller 62:230

Blood 2011;30: 361 2011;30: o AJ, Bose P, Kontoyiannis DP. Breakthrough fungal infections in leukemia infections fungal Breakthrough DP. Kontoyiannis AJ,P, o Bose

- host disease. host disease. -

2010;116: 5111 2010;116: 236. Clin Infect Dis Infect Clin nazole. nazole. - 67.

of Cancer consensus criteria. criteria. consensus Cancer of

- -

Aslam S, Reed SL, Hoenigl M. Point M. SL,Hoenigl Reed Aslam S, NDICU) project. project. NDICU) specific Lateral Flow device test in Bronchoalveolar Lavage. Lavage. Bronchoalveolar testin device Flow specific Lateral 74. - Neutropenic Patients: Aspergillus Galactomannan Lateral Lateral Galactomannan Aspergillus Patients: Neutropenic - - Isakov L, et al. A 2010 working formulation for the for working L,etformulation A al. Isakov 2010 year retrospective study. study. year retrospective Ann Intern Med Intern Ann - N En N Clin Infect Dis Infect Clin

, et al. The strategy for the diagnosis of invasive pulmonary ofinvasivepulmonary thefor diagnosis strategy The , et al. controlled, non controlled, References gl JMed gl -

2002;34: 7 2002;34: 8. Blood

N Engl J Med Engl J N eakthrough Invasive Mold Infections in the in Infections Mold Invasive eakthrough

Clin Infect Dis Clin Infect

Mycoses

2007;356: 335 2007;356:

2012;119: 1831 2012;119: 2018

2015;162: 81 2015;162: - - inferiority trial. inferiority 14. ;67:1610

- cell transplantation. transplantation. cell

2007;356: 348 2007;356: 201 Clin Infect Dis Infect Clin Med Mycol Med - 9; 62:310 blind trial of fluconazole versus fluconazole of trial blind

2008;46: 1813 2008;46: Infectious Diseases Mycoses Mycoses Diseases Infectious - - 47. Clin Infect Dis Clin - 1613. - 9. 7; quiz 7; quiz 956. -

em cell transplants: an an cell transplants: em

of care Diagnosis of careof Diagnosis Lancet zole for antifungal antifungal zole for

-

319 - 2018;56: 406 2018;56: 59.

2008;47: 674 2008;47:

2016;387: 760 2016;387: .

-

Br JHaematol Br 21.

2018;67: 1621 2018;67:

J Antimicrob J Antimicrob J Hear - 15. - 83.

- 9. t

- This article isThis article 33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18

Accepted Article Walsh TJ, Pappas P, Winston DJ, et al. Voriconazole compared with liposomal amphotericin B amphotericin liposomal with compared Voriconazole DJ,etal. P,Winston TJ, Pappas Walsh 573. 1999: Antimicro on Conference Interscience Definitions New, for Standardized Proposal Consensus (IFI): Infections Fungal Invasive on Research inClinical Used Definitions of Analysis JE,et al. B,Bennett dePauw Ascioglu S, 1391 2004;351: neutropenia. and fever with persistent inpatients therapy empirical antifungal for B amphotericin liposomal versus Caspofungin etal. GR, H, TJ,Donowitz Teppler Walsh S127 2019;57: AnItalia chemotherapy: intensive after prophylaxis primary triazole mould active receiving patients myeloid leukemia inacute diseases fungal invasive A, al. et Breakthrough A,Candoni Girmenia C,Busca 510 2012;39: mali withhaematological inpatients mould infections invasive and concentrations plasma Posaconazole etal. HJ, RB, Salzer M, Raggam Hoenigl 2634 2016;71: high in infections fun breakthrough invasive on study Acohort B,et al. JJ,Liss Vehreschild Biehl LM, print] aheadof [Epub 10.1093/cid/ciz282. and he malignancies p Y, etal.Isavuconazole DS,Zhao L,Perlin Fontana study. observational centre real malignancies: with haematological in patients O,Orth Angelova D, Nachbaur year period. a12 over chemotherapy cytotoxic undergoing syndrome myeloid leukemia/myelodysplastic prophyla Ananda 2268 study. observational retrospective institutional centre antif receiving patients high in strains ofresistant emergence and colonization fungal infections, breakthrough J,Auberger Lass a4 prophylaxis: primary posaconazole receiving in patients fungaldisease invasive Breakthrough G, al. et Socie E, Raffoux Lerolle N, cohort. AML Cologne acut with patients in prophylaxis posaconazole of effectiveness Clinical H, et al. MJ,Wisplinghoff Rüping JJ, Vehreschild malignancies. hematological preve inthe posaconazole versus voriconazole efficacy of and the safety Comparing Y, et al. A,Numan R,Assaf Hachem ibrutinib. treated with in patients A,Prot Ghez D,Calleja together. about working leadership is New worldwide: research careand patient to improve Mycology Medical of Confederation M, G Hoenigl f OA, Lass Cornely Med fever. persistent and neutropenia patientswith in therapy antifungal empirical for ungal diseases diseases ungal

- 2002 73. protected byprotected copyright. All rightsreserved. - Rajah MR, Grigg A, Downey MT, et al. Comparative clinical effectiveness of of effectiveness clinical etComparative MT, al. Downey MR,Grigg A, Rajah

ctic voriconazole/posaconazole to fluconazole/itraconazole in patients with acute with acute inpatients to fluconazole/itraconazole ctic voriconazole/posaconazole ;346: 225 ;346:

Haematologica angneux JP, Segal E, et al. Global guidelines and initiatives from the European European the initiativesfrom and Global guidelines etal. E, Segal JP, angneux - 3. - - s37. 41. - - - 402.

- Florl C, Aigner M, Clausen J, Gastl G, Nachbaur D. Invasive fungal fungal Invasive D. Nachbaur GastlG, J, C,AignerM,Clausen Florl Guiding experts and patients towards excellence. excellence. towards patients and experts Guiding - Florl C, Lagrou K, Arsic C,Lagrou Florl risk patients receiving antifungal prophylaxis. prophylaxis. antifungal patientsreceiving risk

- 34. matopoietic

J Antimicrob Chemother Antimicrob J in C, et al. Earlyet in C,al. ungal prophylaxis with posaconazole: real withposaconazole: prophylaxis ungal

n consensus agreement on definitions and management. management. and definitions agreement on consensus n ntion of invasive fungal infections in high in infections fungal ntion ofinvasive

Eur JHaematol Eur 2012;97: 459 2012;97: Int J Antimicrob Agents Antimicrob Int J - Holler D, et D, Holler - e myelogenous leukaemia (AML): a 6 year experience of the ofthe experience a6year (AML): leukaemia e myelogenous cell transplant recipients. recipients. celltransplant Blood bial Agents and Chemotherapy and Agents bial - Mycoses - onset invasive aspergillosis and other fungal infections infections fungal andother aspergillosis invasive onset year study. study. year -

2018;131: 1955 2018;131: Arsenijevic V, Hoenigl M. Improving outcome of outcome M.Improving Hoenigl Arsenijevic V, - .

63.

al. Primary antifungal prophylaxis with micafungin micafungin with prophylaxis antifungal Primary al.

2015;94: 258 2015;94:

2010;65: 1466 2010;65:

2018 - rophylaxis in patients with hematologic hematologic with patients in rophylaxis Clin Microbiol Infect Microbiol Clin life data from a retrospective single retrospective a data from life

; 61:885 ; 2017;50: 384 2017;50: gnancies. gnancies.

J Antimicrob Chemother J Antimicrob - 9. - 64.

Clin Infect Dis Infect Clin - -

894 71. Int J Antimicrob Agents JAntimicrob Int J Antimicrob Chemother Antimicrob J

- . life data from a single datafrom life - 8. Mycoses - : San Francisco, USA, Francisco, : San risk patients with risk patients

2014;20: O952 2014;20:

2019

2017;60: 420 2017;60: ; doi: ; doi:

2012;67: 2012;67: N Engl J Med J Engl Med Mycol Med gal N Engl J Engl N 39th 39th - - 9.

- - risk

- 5.

-

This article isThis article 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34

Accepted Article Leon C,Ruiz Leon Dis Patients. ICU ofAustralian Cohort Prospective Multicenter Froma Risk 3 Levelsof Unit (ICU) f ofRisk Dichotomization Problematic M,etal. Jones EG, J, Lipman Playford infections. fungal secondary for ICU MG. Netea BJ, F,Kullberg Venet G, Monneret unit. care intensive in the aspergillosis Invasive E. Wijngaerden J,Maertens K,Van W, Lagrou Meersseman immunosuppression. tilting seesaw: toward TA. sepsis The JE,Ferguson CM,McDunn Coopersmith RS, Hotchkiss 3,randomised aphase (SECURE): fungi filamentous other and byAspergillus caused disease mould invasive of treatment Maertens trial). (AmBiLoad dosing standard ahigh comparing trial randomized infection:a mold invasive for initial therapy B as amphotericin M, Liposomal et al. J,Maertens OA,Bresnik Cornely aspergillosis. invasive of primary therapy amphoteri versus etVoriconazole al. TF, Patterson DW, R, Denning Herbrecht 350 recipients. stemcelltransplant haematopoietic allogeneic Ka Oshima K, 1366 2011;96: e theHEMA infections: offungal management the therapy in pre versus ofempirical andefficacy use A, etThe M, al. L,Caira Nosari Pagano feasibilit aprospective infection: fungal forinvasive risk athigh patients neutropenic in therapy antifungal based preemptive tomography computed and Galactomannan etal. G, K,Verhoef J,Theunissen Maertens Dis Int J Infect randomize aprospective patient: neutropenic febrile persistently inthe antifungals Galactomannan NL, etal. JG, Chlebicka Tan BH,Low study. feasibility aprospective patients: neutropenic in approach antifungal driven diagnostic Clinically GentileG,et Micozzi al. A, Girmenia C, trial. controlled arandomised patients: haematology direc for histology and culture versus PCR and Galactomannan TC,et al. Sorrell ChenSC, CO, Morrissey Transplant Marrow Bone reduced following fungal invasive infection for PCR Randomized et al. L, M, Klingspor O,Remberger Blennow after allo PCR comparing Apr T, et al. L,Klingebiel H, Klingspor Hebart 1042 2009;48: high therapy for antifungal preemptive versus Empirical S,et al. C,Maury Pautas C, Cordonnier StudyGroup. Mycoses Diseases Infectious Allergy of and Institute National andneutropenia. fever persistent with patients in empirical therapy Bfor amphotericin Liposomal etal. C, RW,Arndt TJ, Finberg Walsh Crit Med Crit Care colonization. with Candida ill critically patients innonneutropenic treatment early antifungal

2016;63: 1463 2016;63: - - 5. risk, febrile, neutropenic patients: a randomized, controlled trial. trial. controlled a randomized, patients: neutropenic risk, febrile,

protected byprotected copyright. All rightsreserved. -

SCT. SCT. - JA, Raad, II, Marr KA, et al. Isavuconazole versus voriconazole for primary primary for voriconazole versus Isavuconazole KA, et al. Marr Raad, II, JA, Acquired Invasive Candidiasis: Results Using a Risk Using a Results Candidiasis: Invasive Acquired - Santana S, S S, Santana nda Y,Asano

2006;34: 730 2006;34: - - 2011;15: e350 2011;15: Bone Marrow Transplant Marrow Bone 70. 51. - based and empirical treatment with liposomal amphotericin B in patients in amphotericinB liposomal with empiricaltreatment based and - ting use of antifungal treatment for invasive aspergillosis in high aspergillosis forinvasive treatment antifungal useof ting

9. Clin Infect Dis Clin Infect

Nat Med Nat aavedra P, et al. A bedside scoring system ("Candida score") for for score") ("Candida system scoring bedside P,etA al. aavedra

2010;45: 1710 2010;45: - Mori Y, et al. Presumptive treatment strategy for aspergillosis in foraspergillosis strategy treatment Presumptive et Mori Y, al. - 7. - 6.

2009;15: 496 2009;15:

Med Mycol Med N Engl J Med EnglJ N y study. y study. -

2007;45: 205 2007;45: controlled, non controlled, Clin Infect Dis Infect Clin

- 2009;43: 553 2009;43: 8. Clin Infect Dis Clin N Engl JMed N

2011;49 Suppl 1: S17 Suppl 1: 2011;49 - ospective randomized controlled trial trial controlled randomized ospective 7.

1999;340: 764 1999;340: -

- intensity conditioning and hematopoietic SCT. SCT. hematopoietic and conditioning intensity

16. 2007;44: 1289 2007;44: - - inferiority trial. inferiority acquired immunosuppression and the risk therisk and immunosuppression acquired

- guided preemptive vs. empirical vs.empirical guided preemptive J Clin Oncol J Clin - Lancet Infect Dis Lancet Infect

61.

2002;347: 408 2002;347: 2005;41: 1242 2005;41:

J Antimicrob Chemother J Antimicrob - - 7 - - loading dose regimen with with regimen dose loading Predictive Model to Categorize to Categorize Model Predictive - Chart Project. Project. Chart 1. - based therapy based 97.

- 2010;28: 667 2010;28: 23. Lancet

- -

15. 50. 2013;13: 519 2013;13: Clin Infect Dis Infect Clin

2016;387: 760 2016;387:

or Intensive Care Care Intensive or Haematologica and risk factors risk factors and cin B for cin Bfor - - emptive emptive 74.

Clin Infect Clin Infect -

risk 2007;60: 2007;60: d study. study. d -

28. - -

9.

This article isThis article 70 69 68 67 66 65 64 63 62 61 60 59 58 57 56 55 54 53 52

Accepted Article Betts RF, Nucci M, Talwar D, et al. A Multicenter, double et AMulticenter, D, al. M,Talwar Nucci Betts RF, 1519 2007;369: double IIIrandomised aphase candidosis: invasive and candidaemia for amp liposomal versus al.Micafungin CA,et da Cunha P, Kuse ER,Chetchotisakd candidiasis. invasive of forms other and candidemia of treatment for caspofungin versus Micafungin RF, etal. Betts PG, Rotstein CM, Pappas candidiasis. invasive for fluconazole versus Anidulafungin PG, al. et Pappas C, Rotstein Reboli AC, intra surgery for of prevention the for therapy antifungal placebo A randomized, S,etal. Utzolino JL, W,Vincent Knitsch Suppl7:19 2012;18 2012:non diseases Candida of management an forthe diagnosis guideline al. ESCMID T,et M,Bassetti OA, Calandra Cornely Clinical Trial. Randomized TheEMPIRICUS Failure: Organ Multiple Inva Without Survival and Treatment Micafungin Empirical etal. C, E,Schwebel Timsit JF,Azoulay trial. arandomized patients: unit care intensive E MG, Schuster high in candidiasis intra prevents prophylaxis al. Fluconazole J, et P,FrancioliBille Eggimann candidalinfe to prevent Double et SM, al. Swoboda CW, Pelz RK,Hendrix samples. lavage bronchoalveolar patients: malignancy inhematological aspergillosis ofinvasive al. Diagnosis J,EiglS, et Heldt S,Prattes Infection Candida Invasive OA, Wispling Koehler FC,Cornely 48 2018;61: spine. vertebral the lumbar of Candidainfection invasive of diagnosis cells the for P.Candida RichterA,Koehler ChangDH, H, OA, Wisplinghoff Koehler FC,Cornely 348 infection. mold pulmonary ofinvasive identification Fungus al. O,et A,Kniemeyer Bacher P,Steinbach clinical trial. a whole blood: in candidemia of diagnosis Ostrosky Clancy CJ, E, Mylonakis study. multicenter aprospective critically illpatients: betw discriminating C,Ruiz Leon trials. prophylaxis in antifungal use criteria systematic for the in infections candidal Ostrosky NI, Paphitou 46 2011;54: care unit. intheintensive candidiasis invasive for onprophylaxis clinicaltrials for Ostrosky care setting. intensive inthe candidiasis invasive nosocomial rulefor prediction a clinical of validation Ostrosky patients with invasive candidiasis. candidiasis. invasive with patients a standar versus treatment regimen caspofungin - sive Fungal Infection in Adults WithICU Adults in Infection Fungal sive 52. protected byprotected copyright. All rightsreserved.

- -

Performance of cytokines, Asp LFD, and Aspergillus PCR in same day blood and day blood same in PCR Aspergillus LFD,and Asp cytokines, of Performance Zeichner L, Pappas PG, Shoham S, et al. Improvement of aclini of Improvement S,etal. PG, Shoham L,Pappas Zeichner retr al. Multicenter et SobelJ, C, L,Sable Zeichner - - - N Engl J Med EnglJ N 52. 51. Santana S, Saavedra P, et al. Usefulness of the "Candida score" for for score" theof "Candida P,etUsefulness al. Saavedra S, Santana Eur J Clin Microbiol Infect Dis Infect Microbiol Eur JClin dwards JE, Jr., Sobel JD, et al. Empirical fluconazole versus placebo for placebo versus fluconazole Empirical etal. JD, JE,Jr.,Sobel dwards -

- 27. abdominal infections. infections. abdominal - risk surgical patients. patients. risk surgical

- innon candidiasis invasive and colonization Candida een 37. - Zeichner L, Rex JH. Rules for identifying patients at increased risk for risk for at increased patients identifying Rulesfor JH. L,Rex Zeichner

ctions in critically ill surgical patients. patients. ill incritically surgical ctions

2007;356: 2472 2007;356: surgical intensive care unit: approach to developing practical practical developing to careapproach unit: surgical intensive - A Prospective Pilot Study. PilotStudy. A Prospective - hoff H, etal.Candida H, hoff Zeichner L, et al. T2 magnetic resonance assay for the rapid the rapid for resonance assay T2magnetic L,etal. Zeichner J Infect Clin Infect Dis Clin Infect Clin Infect Dis Infect Clin

invasive candidiasis following gastrointestinal following gastrointestinal candidiasis invasive Med Crit Care 2018;77: 235 2018;77: -

82. 2007;26: 271 2007;26: - - Acquired Sepsis, Candida Colonization, and Colonization, Candida Sepsis, Acquired neutropenic adult patients. adult neutropenic

Ann Intern Med Intern Ann

- 2009;48: 1676 2009;48: d caspofungin treatment regimen for adult adult for regimen treatment caspofungin d blind placebo blind - specific CD4(+) T cells for rapid cells rapid for T CD4(+) specific Am J Respir Crit Care Med Care Am JRespirCrit Clin Infect Dis Clin Infect

Front Microbiol Front 2015;61: 1671 2015;61: Crit Med Crit Care

- -

41. Reactive T Cells for the Diagnosis of of Diagnosis forthe Cells Reactive T 1999;27: 1066 1999;27: Clin Infect Dis Clin Infect - 6. - blind trial ofahigh trial blind Med Mycol Med

ospective development and and development ospective Ann Surg Ann - - - controlled trial of preemptive preemptive of trial controlled controlled trial of fluconazole fluconazole trial of controlled

84. 2008;149: 83 2008;149:

JAMA 2007;45: 883 2007;45:

- 2009;37: 1624 2009;37: 8.

2018;9: 1381. 2018;9: 2015;60: 892 2015;60: - 2005;43: 235 2005;43: 72.

2001;233: 542 2001;233: -

cal prediction rule rule cal prediction 2016;316: 1555 2016;316: blind trial. trial. blind Clin Microbiol Infect Microbiol Clin

- - abdominal abdominal - dose dose neutropenic neutropenic - 90.

2015;191: 2015;191: hotericin B hotericin d - 93. -

Mycoses reactive T Mycoses - - -

33. 9. Lancet

43.

-

8.

-

64.

This article isThis article 88 87 86 85 84 83 82 81 80 79 78 77 76 75 74 73 72 71

Accepted Article requiring renal replacement therapy. therapy. replacement requiring renal lipid preparation a with prophylaxis IR. Preemptive Marino MM, T, Wagener DL,Gayowski N,Singh Paterson recipients. lung transplant in voriconazole with treatment et Preemptive B, al. GI, Levvey Neoh CF,Snell 346 2007;35: (1 plasma on based infection fungal of treatment M. Preemptive Makuuchi S, J, Tamura Kaneko Y, Sugawara N, Akamatsu Mycol PATHA recipients: transplant organ solid among infections mold invasive of features Epidemiological D. Horn N, FranksB, FP,Azie S,Silveira Husain 1006. high infectionin fungal invasive of the prevention for micafungin of trial Randomized O,etal. A,Cointault Saliba F,Pascher 232 lung in prophylaxis antifungal aerosolized ofam safety Comparative JR. Perfect SM, R,Palmer Davis Jr., Duane E,Benjamin DK, Ashley RH,Drew Dodds era. MELD inthe revisited risk factors V,Ic Saliba F,Delvart 2085 effectiveness. and hepatotoxicity recipients: transplant in lung itraconazole or voriconazole with prophylaxis al. LF, et Antifungal DJ,Angel J,Cadena Levine Recipients. S, Husain analysis. high infectionin fungal invasive Martin Muriel A, J, Fortun high in amphotericin B of formulations lipid with prophylaxis the role of recipients: transplant Martin J, Fortun recipients. high in fungalinfections invasive of prophylaxis for fluconazole versus S, et AP,Pelletier DJ,Limaye Winston America. Societyof Diseases Infectious bythe Update 2016 Aspergillosis: of Management and Diagnosis forthe Practice Guidelines et al. DW, GR,3rd,Denning Thompson TF, Patterson Transplant Heart Lung summary. Executive recipients: organtransplant cardiothoracic and support circulatory fungal of management forthe Guidelines Transplantation Lung Heart for and Society International etThe2015 BD, al. A, Alexander S,Sole Husain recipients. J,In et Fortun al. Y, J,Meije Gavalda 2463 2011;43: recipients. transplant solid organ infectionsin fungal invasive of treatment prevention,and diagnosis, guidelines for al. Italian et BarchiesiF, DD, Gasperina PA, Grossi candidiasis. invasive Mora 230 study. observational aretrospective results of disease: fungal invasive transplant organ post solid for Caspofungin U,etal. J,Schulz Winkler M,Pratschke - - - 7. 7. - risk patients. risk -

91.

Duarte J, Betts R, Rotstein C, et al. Comparison of caspofungin and amphotericin Bfor amphotericin and ofcaspofungin Comparison C,et al. R,Rotstein J,Betts Duarte

2017;55: 269 2017;55: protected byprotected copyright. All rightsreserved.

Liver Transpl

Clin Infect Dis Clin Paterson DL, Studer S, et al. Voriconazole Prophylaxis in Lung Transplant Lung Transplant in Prophylaxis Voriconazole S,etal. DL,Studer Paterson

Clin Microbiol Infect Microbiol Clin Am JTransplant Am Transpl Infect Dis Infect Transpl Am JTransplant Am - 5 - 71. 1. - Davila P, Moreno S, et al. Prevention ofin al. Prevention S,et Moreno P, Davila

of amphotericin B for invasive fungal infections in liver transplant recipients recipients liver transplant in infections fungal Bforinvasive amphotericin of

J Antimicrob Chemother J Antimicrob - 77. N Engl JMed N hai P, et al. Fungal infections after liver transplantation: outcomes and and outcomes livertransplantation: after infections Fungal et al. hai P,

2016;22: 427 2016;22:

2016;35: 261 2016;35:

2016;63: e1 2016;63:

photericin B lipid complex and amphotericin B deoxycholate as deoxycholate B amphotericin and complex Blipid photericin - Davila P, et al. Caspofungin versus fluco versus etCaspofungin P, al. Davila

2014;14: 2758 2014;14: 2006

2013;15: 344 2013;15: -- > 3)beta

2014;20 Suppl 7:27 Suppl 2014;20 - - risk liver transplant recipients. recipients. transplant risk liver score A propensity recipients: transplantation risk liver ; 6:3008

2002;347: 2020 2002;347: - - vasive fungal infections in solid organ transplant transplant organ solid in infections fungal vasive - 35. e60. 82. Transplantation al. Randomized, double Randomized, al. Clin Transplant Clin -

D

- - - - 16 - glucan levels after liver transplantation. transplantation. afterliver levels glucan recipients. transplant

53. 64. 2003;52: 813 2003;52: .

- 9. - 48.

2013;27: E454 2013;27:

2001;71: 910 2001;71:

- 9.

infections in mechanical inmechanical infections vasive fungal infections inliver infections fungal vasive

lliance(R) registry analysis. analysis. registry lliance(R) - Transpl Dis Transpl Infect blind trial of anidulafungin trial ofanidulafungin blind Am J Transplant Am Clin Infect Dis Clin Infect Transplantation nazole as prophylaxis of of prophylaxis nazole as - - 3. 61. -

risk liver transplant transplant liver risk

Transplant Proc Transplant

2015;60: 997 2015;60:

2009;9: 2009;9: 2010;12: 2010;12:

2004;77: 2004;77: Infection Med J -

This article isThis article 109 108 107 106 transplantation. 105 104 103 102 101 100 99 98 97 96 95 94 93 92 91 90 89

Accepted Article

Garcia dermatitidis. Exophiala and rubrum, Trichophyton albi Candida Aspergillus fumigatus, in attributes selected of virulence Overview S,IlkitM. Seyedmousavi H,MetinDogen A, B, Boral 1646 2015;211: Solid After Infection Mold to Invasive Susceptibility DEFB1Polymorphism IL1Band et T,al. Lecompte MS, Gresnigt A, Wojtowicz aspergill invasive to influence susceptibility alleles Plasminogen et al. G,JW, AK, Liao Chien Zaas stem Toll KA,etal. Marr ChienJW, PY, Bochud 2018;56. Biomarkers. Diagnostic withEarly RiskFactors Genetic and Clinical Combining Predictin RA. Barnes C, Parr White PL, resistance. echinocandin of reservoir isahidden candidiasis CJ. EG,Abdominal MH, Press Clancy RK, Nguyen Shields and A Source Control al. Intra RK,et Shields CJ, Vergidis P,Clancy Strategies. Multidrug Emergence of LiverTransplantation: After Site Infections Surgical L, et al. JA,Clancy CJ, Clarke Viehman candidemia. breakthrough and with cancer O Uzun therapies. spectrum antifungal G,Garcia Cuervo Dis Ris AL. Nucci M,Colombo Hospital. Japanese in a Recipients Transplant Cell Stem Hematopoietic Allogeneic in Candidemia Breakthrough Kim Mycoses infections. fungal invasive breakthrough to approach TF. Our2014 G,Patterson Maschmeyer Dis infections. fungal and syndrome reconstitution Immune N. Singh Gupta AO, Dis malignancies. hematological patients with in prophylaxis antifungal secondary of efficacy andthe aspergillosis relapsing regarding issues Clinical DP. NV,Kontoyiannis Sipsas neutropenia. with patients scan tomography computed thoracic onsequential aspergillosis pulmonary invasive of characteristics changing volumeand Increasing BernardA,et al. JF, D,Couaillier Caillot Radiol al tomography computed by volume lesion pulmonary of al. Serialassessment et Groll AH, CP, Heussel JJ, Vehreschild 1 2008;27: transplantation. thoracic organ after aspergillosis invasive of f as al. Caspofungin T, Wittwer et I, J, Kaczmarek Groetzner on Recovery of theof beta Recovery on V,Wag Loiko Infect Dis Cunha C, Aversa F, Lacerda JF, et al. Genetic PTX3 deficiency and aspergillosis instem aspergillosis and deficiency PTX3 Genetic JF,et al. F,Lacerda C,Aversa Cunha

2002;21: 209 2002;21: 527 2011;24: 1584 2006;42: ura M, Araoka H, Yamamoto H, et al. Clinical and Microbiological Characteristics of of Characteristics andMicrobiological Clinical H,etal. H,Yamamoto M, Araoka ura - cell transplantation. transplantation. cell

-

2017. Vidal C, Viasus D, Carratala J. Pathogenesis of invasive fungal infections. infections. fungal ofinvasive J. Pathogenesis Carratala D, Viasus C, Vidal , Ascioglu S, Anaissie EJ, Rex JH. Risk factors and predictors of outcome patients in outcome of andpredictors Risk factors RexJH. EJ, S, Anaissie , Ascioglu protected byprotected copyright. All rightsreserved. osis. osis.

N Engl J Med Engl J N

2014;57: 645 2014;57:

2013;26: 270 2013;26: - Transplantation 6.

ener J. The Paradoxical Effect of Echinocandins in Aspergillus fumigatus Relies in fumigatus Aspergillus ofEchinocandins Effect Paradoxical The ener J.

PLoS Genet PLoS - 57. - - - 11. 33. Vidal C, Nucci M, et al. Breakthrough candidaemia in the era of broad era of inthe candidaemia Breakthrough Nucci M,et al. Vidal C, - 91. Antimicrob Agents Chemother Agents Antimicrob

ntifungal Treatment. Treatment. ntifungal

2014;370: 421 2014;370: - - 51. 6. - -

1,3 Resistant Bacteria and Implications for Prophylaxis and Treatment Treatment and forProphylaxis Implications and Bacteria Resistant 2008;4: e1000101. 2008;4: Antimicrob Agents Chemother Agents Antimicrob lows survival prediction in invasive pulmonary aspergillosis. aspergillosis. pulmonary invasive predictionin survival lows k factors for breakthrough candidemia. candidemia. breakthrough for k factors

N Engl JMed N

J Clin Oncol J Clin 2016;100: 2107 2016;100: - Glucan Synthase Fks1. Fks1. Synthase Glucan Clin Microbiol Infect Microbiol Clin - 32. g Invasive Aspergillosis in Hematology Patients by by Patients inHematology Aspergillosis g Invasive

2001;19: 253 2001;19:

2008;359: 1766 2008;359:

- like receptor 4 polymorphisms and aspergillosis in aspergillosis and 4polymorphisms like receptor PLoS One PLoS - - Clin Infect Dis Infect Clin Abdominal Candidiasis: The Importance of Early ofEarly Importance The Candidiasis: Abdominal

14.

cans, Cryptococcus neoformans, neoformans, Cryptococcus cans,

2017;61. Fungal Genet Biol Genet Fungal -

Antimicrob Agents Chemother Agents Antimicrob Organ Transplantation. Transplantation. Organ

2016;22: 181 2016;22: - 2016;11: e0153247. 2016;11: 9.

- 2014;58: 7601 2014;58: 77.

2001;32: 1713 2001;32:

irst

J Heart Lung Transplant J Heart Lung - line therapy for the treatment the treatment therapyfor line - Eur J Clin Microbiol Infect Infect Microbiol Eur JClin 8.

2018;111: 92 2018;111: - 5. -

7.

J Infect Dis Infect J s Increase s Increase Curr Opin Infect OpinInfect Curr J ClinMicrobiol J Curr Opin Curr Clin Infect Clin Infect

- 2017;61. 107. s in s in

- Eur cell cell

-

This article isThis article Accepted127 126 125 124 123 122 121 120 119 118 Article117 116 115 114 113 112 111 110

plasma concentratio plasma voriconazole inadequate for factors Potential et al. RB, Raggam W, M, Hoenigl Duettmann 4793 monitoring. drug therapeutic and pharmacokinetics LG Ng K, Pont SC, JE, MJ,Ray Chen Dolton Chemother J Antimicrob infection. of models in experimental aspergillosis invasive of the outcome therapy influences Barchiesi F,Sa Infect Dis study. cohort aretrospective utilization: hospital resource ICU and inthe candidemia for therapy antifungal empiric al. Inappropriate H, Arnold et KollefMH, MD, Zilberberg with caspofung treated patients in infections mould invasive etBreakthrough FekkarA, al. C, Godet Pang KA, 2017;19. center. celltransplant large ina stem infections yeast bloodstream CA. Santos R, Romee LR, Pande A, Non a Re on Review aSystematic Infection: Trichosporon Invasive C. Hennequin JN, Junior de Almeida Agents Chemother of dose alow with prophylaxis during glabrata resistant Candida Jimenez Bizerra FC, management. and mechanisms, prevalence, resistance: Perlin DS,Rautemaa Study. AComparative Species: Pseudallescheria/Scedosporium Rollin 1583 2016;162: viaironsequestration. metabolism fumigatus inhibitsAspergillus aeruginosa byPseudomonas produced bacteriophage PR,etal.Pf4 JA,Secor JC, Ferreira Penner Microbiology i phage Pseudomonas PR,etal. Secor LM, Nazik H,Joubert 362 Mold Useof theClinical WeRetain Can fumigatus: Aspergillus in Resistance JF.Azole Meis Melchers WJ, A, Verweij PE,Chowdhary neoformans. Cryptococcus in voriconazole and to fluconazole etal.Heteroresistance G, R, Amalfitano Petter Mondon P, Persistence. glabrata Cli Candida among Phenotype Distributed Ben zygomycosis. models of and murine following organisms Zygomycetes virulence of Ben GA, Lamaris 7830 2015;59: oryzae. Rhizopus of and Virulence onSusceptibility Triazoles o DP.Effect Kontoyiannis WalshTJ, RE, ND,Lewis Albert Bellanger AP, 17 Remodeling. Wall and Cell FKSGenes of Expression Govern That Mechanisms Distinctive Three Least with at Associated L, W Zhang Yang F, malignancies. malignancies. .

- - - 8. Ami R,Zimmerm - emerging Fungal Pathogen. Pathogen. Fungal emerging - 9. Pinheiro R, de Meirelles JV, Vila TVM, et al. Biofilm Formation by by Biofilm Formation TVM, et al. JV,Meirelles Vila R,de Pinheiro protected byprotected copyright. All rightsreserved.

2010;10: 150. 2010;10: MBio

2017;163: 1568 2017;163: Antimicrob Agents Chemother Agents Antimicrob ntinelli A, Biscotti T, Greganti G, Giannini D, Manso E. Delay of antifungal antifungal E.Delayof Manso D, Giannini G, T, Greganti ntinelli A,Biscotti - 2. in. in. - - 9

Ami R, Lewis RE, Chamilos G, Samonis G, Kontoyiannis DP. Increased Increased DP. G, Kontoyiannis G, Samonis Chamilos RE, Ami R,Lewis 4.

J Infect J 2016;7

akabayashi H, et al. Tolerance to Caspofungin in Candida albicans I albicans Candida in Caspofungin to H, al.Tolerance et akabayashi 2014;58: 2438 2014;58: -

Ortigosa C, Souza AC, et al. Breakthrough candidemia due to multidrug to due candidemia Breakthrough AC,et C,Souza al. Ortigosa - ns in intensive care unit patients and patients with hematological with hematological patients and unitpatients care intensive ns in Richardson R, Alastruey Richardson an O, Finn T, et al. Heteroresistance to Fluconazole Is a Continuously Is aContinuously to Fluconazole Heteroresistance et FinnT, al. O, an

2016;71: 2230 2016;71:

; doi:10.1128/mBio.00655 ; 2012;64: 424 2012;64: Antimicrob Agents Chemother Agents Antimicrob Antimicrob Agents Chemother Agents Antimicrob - 77. Front Microbiol Front

- 40. J Infect Dis J Infect

- Pseudozyma and other non other and Pseudozyma - - 3. 9. Active Antifungal Azoles? Antifungal Active

, McLachlan AJ. Multicenter study of voriconazole voriconazole of Multicenter study AJ. McLachlan ,

- 2013;57: 3262 2013;57: Izquierdo A. The global problem ofan problem A.global The Izquierdo exposure to voriconazole: a study involving fly fly involving astudy to voriconazole: exposure

2009;199: 1399 2009;199:

2016;7: 1629. 2016;7: nical Strains Associated with In with Vivo Associated Strains nical - Antimicrob Agents Chemother Agents Antimicrob 16

.

Lancet Infect Dis Infect Lancet

2017;61 1999;43: 1856 1999;43: nhibition of Candida albicans. albicans. ofCandida nhibition - 7. Antimicrob Agents Chemother Agents Antimicrob

- Front Microbiol Front 406.

micafungin. micafungin. ; doi:10.1128/AAC.00071 ; Clin Infect Dis Clin Infect - Candida opportunistic opportunistic Candida Transpl Infect Dis Infect Transpl

f Preexposure to f Preexposure -

2017;17: e383 2017;17: 61.

Microbiology Antimicrob Antimicrob

2017;8: 1568. 2017;8: 2016;62: 2016;62:

2012;56: 2012;56: tifungal tifungal

s BMC - e92.

-

-

This article isThis article Accepted148 147 146 145 144 143 142 141 140 139 138 137 136 Article135 134 133 132 131 130 129 128

Debruyne D, Ryckelynck JP. Clinical pharmacokinetics of fluconazole. fluconazole. of pharmacokinetics JP. Clinical D,Ryckelynck Debruyne T Stem Cell orPeripheral Marrow aBone Undergoing Patients inAdult Infections Fungal of Prophylaxis for Alone Fluconazole versus with Fluconazole inCombination Micafungin of Study J Hiemenz 159 2011;16: theliterature. reviewof candidosis: ofinvasive treatment inthe micafungin and caspofungin ofanidulafungin, andmetabolism M. Pharmacology Ruhnke G,Kofla p ICU in ofcaspofungin Pharmacokinetics HJ,et al. Leeuwen van JA, Schouten Muilwijk EW, rifampin. nelfinavir or and caspofungin between forinteractions Potential L,etal. EM,Hickey Migoya JA, Stone men. healthy in caspofungin al. Single PJ,et SD,Wickersham JA, Holland Stone 2004;44: antifungal. anechinocandin anidulafungin, of analysis pharmacokinetic Population HenkelT. D, M,Krause Stogniew T, Ludden JA,W, Dowell Knebel Mycol A.Aspergillus M,Beauvais FM, Seidler Muller Infections. Related Biofilm Aspergillus) (and Against Candida Strategies Therapeutic on Updates M. FK,Ghannoum Muakkassa signi and industrial R, Gutierrez G,Rajendran Ramage Spectr Microbiol J,Mu Chandra 1 2016;931: Disease. inHuman Biofilms G. R, Ramage Aspergillus Rajendran Williams C, a casereport. and cases 72 including review literature F,Rodriguez Cobo Dis Catheter Vascular Ro Katragkou A, malignancies. with haematological inpatients concentrations plasma posaconazole low on education on personal structured of Impact et al. RB, Raggam W, M, Hoenigl Duettmann concentration. exposure monitoring: drug therapeutic ofposaconazole study AJ. Multicenter McLachlan L, Ng K, Pont SC, JE, MJ,Ray Chen Dolton diseases. and infectious microbiology inclinical guidelines European 2012:developing diseases Candida of management and the diagnosis guideline for al.ESCMID* JP,et OA, Donnelly Cornely AJ, Ullmann patients. transplant cell stem hematopoietic and in leukemia mucormycosis and aspergillosis candidiasis, ECIL L,etal. S,Pagano F, Agrawal Tissot i12 pharmacodynamic and pharmacokinetic disease: and infections mould forinvasive monitoring drug Therapeutic WW. Hope KE, Stott isav A, Schmitt Bohme OA, Cornely 10 1993;24: Jenks JD, Hoenigl M. Treatment of Aspergillosis. Aspergillosis. of Treatment M. JD, Hoenigl Jenks atients. atients.

- 2015;61 Suppl 6: S622 Suppl 6: 2015;61 i8. uconazole as antifungal prophylaxis in acute myeloid leukemia patients with patients leukemia myeloid inacute prophylaxis antifungal uconazole as

2011;49 Suppl 1: S96 Suppl1: 2011;49 protected byprotected copyright. All rightsreserved.

J Antimicrob Chemother Antimicrob J 590 , Cagnoni P, Simpson D, et al. Pharmacokinetic and Maximum Tolerated Dose Dose Tolerated Maximum and Pharmacokinetic D,etal. P,Simpson , Cagnoni ransplant. ransplant. - - 27. 11. - - 8. 66. Int J Antimicrob Agents Antimicrob Int J kh Antimicrob Agents Chemother Agents Antimicrob

ilides E, Walsh TJ. Role of Echinocandins in Fungal Biofilm Fungal in Echinocandins of TJ. Role E, Walsh ilides

erjee PK. Candida Biofilms: Development, Architecture, and Resistance. andResistance. Architecture, Development, Biofilms: Candida PK. erjee 2015;3

- - Related Infections, Immunomodulation, and Mucosal Surfaces. Surfaces. Mucosal and Immunomodulation, Infections, Related ficance. ficance. Candida et al. EM, J,Granger Lopez Haematologica Antimicrob Agents Chemother Agents Antimicrob Antimicrob Agents Chemother Agents Antimicrob ;

doi: 10.1128/microbiolspec.MB doi: - 9. FEMS Microbiol Lett Microbiol FEMS - s100.

Antimicrob Agents Chemother Agents Antimicrob - Hoffmann A, Ullmann AJ. Safety and pharmacokinetics of of pharmacokinetics AJ. and Safety A,Ullmann Hoffmann

2014;69: 3294 2014;69: - Correa M, Jones B, Williams C. Aspergillus biofilms: clinical clinical biofilms: Aspergillus WilliamsC. B, M,Jones Correa

2017;102: 433 2017;102:

2014;44: 140 2014;44: Clin Microbiol Inf Microbiol Clin - Adv Exp Med Biol Med Adv Exp - response relationship and factors affecting factors and relationship response 6 guidelines for the treatment of invasive invasive of the treatment 6 guidelinesfor considerations. considerations.

fumigatus biofilms in the clinical setting. setting. the clinical in biofilms fumigatus 2012;56: 55 2012;56:

2011;324: 89 2011;324: - J Fungi (Basel) J Fungi 9. -

- and multiple and

- 44. 4.

2005;49: 1331 2005;49:

2004;48: 4306 2004;48:

-

Infect Dis(Lond) Infect in ect

- duced prosthetic joint infection. A infection. joint prosthetic duced J Antimicrob Chemother J Antimicrob 2016;931: 95 2016;931: 0020 03

2012;18 Suppl 7:1 Suppl 2012;18

2002;46: 739 2002;46: - - 10. 97. -

2015 2018;4 -

dose pharmacokinetics of pharmacokinetics dose

- - 6. . 14.

Clin Pharmacokinet Clin

: 98 -

103. 2017;49: 81 2017;49:

J Clin Pharmacol J Clin - - 45. . Related Disease: Disease: Related

Adv Exp Med Biol Exp Med Adv Eur J Med Res JMed Eur

- 8. - site patient site patient

2017;72: 2017;72: Clin Infect Clin Infect - 94. Med

This article isThis article Accepted165 164 163 162 161 160 159 158 157 156 Article155 154 153 152 151 150 149

Ayestaran A, Lopez RM, Montoro JB, et al. Pharmacokinetics of conventional formulation formulation conventional of al. Pharmacokinetics JB, et Montoro RM, Lopez A, Ayestaran volunteers. compl lipid B amphotericin of pharmacokinetics tolerance, and safety, al.Comparative et MA, Amantea JE, Kan VL,Bennett voriconazole. of profile H.Pharmacokinetic/pharmacodynamic F,Derendorf Ihle U, Theuretzbacher Chemother in adults. ofvoriconazole pharmacokinetics Population Hope WW. Steady Five Predict t Three Days on Concentrations Plasma M. Posaconazole Hoenigl W, J,Duettmann Prattes Agents Chemother healthy adults. in doses multiple and in single administered posaconazole oral V. Batra Phar M,Lim J, R,PaiS,Laughlin Courtney Agents Chemother following single posaconazole Kri suspension. to oral relative capsule formulations tablet and innew posaconazole of pharmacokinetics Single E. M,O'Mara Martinho MaL, Krishna G, 30. volunteers. healthy in safety and pharmacokinetics rising tosingle trial investigate clinical arandomized posaconazole: of tablet formulation solid oral new A O'MaraE. RA, M, Preston Martinho MaL, Krishna G, patients. of optimized treatment for implications practical drugs: ofantifungal P. Pharmacokinetics R, Smuszkiewicz Bellmann Suppl1:e1 2018;24 ESCMID ofthe2017 summary executive diseases: JM,Arikan Aguado AJ, Ullmann Pharmacol Clinical pharmac R. Bellmann Chemother Agents Antimicrob Fungi. Other Filamentous and Aspergillus to Due Infections with Invasive in Patients Attainment andTarget in Trials Adults 3(SECURE) Phase 1and Phase from Isavuconazole of Pharmacokineti Population R, Bonate PL. Q,Townsend Lu D, L,Kowalski A,Kovanda Desai Rats. to Sulfate I Schmitt therapy. in andplace development, design, mucormycosis: and aspergillosis invasive of the treatment M. Spotl Hoenigl D, R, J, Buchheidt Krause HJ, JD, Salzer Prattes Jenks volunteers. inhealthy BAL8557, prodrug, ofits administration oral and infusion intravenous after BAL4815 triazole the newantifungal Schmitt Study). the VITAL (Resultsfrom FungalDisease with Invasive in Patients Estimation Nonparametric Pharmacokine Population Q, etal.Isavuconazole AV,Lu Desai LL, Kovanda 2078 2015;59: study. escalation 2,dose aphase results of neutropenia: Antimicrob Agents Chemother Agents Antimicrob ofpatien agroup Bin amphotericin of formulation fatemulsion versus savuconazole following Single and Repeat Repeat Oral and Single following savuconazole eter P, Flannery B, Musick T, Gohdes M, Martinho M, Courtney R. Disposition of R.Disposition M, Courtney M,Martinho Gohdes T, Musick Flannery B, eter P,

protected byprotected copyright. All rightsreserved. Antimicrob Agents Chemother Agents Antimicrob - - Hoffmann A Hoffmann Multiple etal. Maares J, RoosB, A, Hoffmann Drug Des Devel Ther DesDevel Drug

2007;2: 37 2007;2: 2012;56: 526 2012;56: J Infect J Infect Dis Antimicrob Agents Chemother Agents Antimicrob Clin Pharmacokinet - 85. Antimicrob Agents Chemother Antimicrob

- 2003;47: 2788 2003;47: 3543 2004;48: State Levels. State Levels. - H, Kato K, Townsend R, et al. Tissue Distribution and Elimination of Elimination and Distribution al.Tissue R,et K, Townsend H, Kato e38. -

58. 1991;164: 418 1991;164: -

31.

okinetics of systemically administered antimycotics. antimycotics. administered systemically of okinetics

ex and amphotericin B desoxycholate in healthy male inhealthy B desoxycholate amphotericin and ex - 1033 2018;12:

dose oral administration in healthy subjects. subjects. inhealthy administration oral dose 2016;60: 5483 2016;60: 1996;40: 609 1996;40: - Akdagli S, et al. Diagnosis and management of Aspergillus Aspergillus andmanagement of Diagnosis S, et Akdagli al. Antimicrob Agents Chemother Agents Antimicrob

Infection - - 2006;45: 649 2006;45: 95. 51.

-

21. 2016;60: 4568 2016;60:

Antimicrob Agents Chemother Antimicrob

2017;45: 737 2017;45: 2012;56: 4196 2012;56: - - 12. 44. - 91.

2017;61 - - - dose phase I study to evaluate the to evaluate Istudy phase dose

63. Dose Administration of Isavuconazonium Isavuconazonium of Administration Dose

macokinetics, safety, and tolerability tolerability of and safety, macokinetics, - ECMM

J Antimicrob Chemother J Antimicrob - 76. -

dose pharmacokinetics and safety of and safety pharmacokinetics dose ;

doi: 10.1128/AAC.01292 -

79. Antimicrob Agents Chemother Agents Antimicrob - - ERS guideline. ERS guideline. 201.

2016;60: 5595 2016;60: Antimicrob Agents Antimicrob -

and multiple and ight on isavuconazole in isavuconazole ight on ts with neutropenia. neutropenia. ts with

2006;50: 286 2006;50: Clin Micr Clin tic Analysis Using Using Analysis tic Antimicrob Antimicrob

20 - Antimicrob Antimicrob 12;67: 2725 12;67: 9. -

- 17 obiol Infect Curr Clin Curr dose dose .

- 93.

cs o -

This article isThis article Accepted 183 182 181 180 179 178 177 176 175 174 Article173 172 171 170 169 168 167 166

albicans and Candida glabrata. glabrata. Candida albicans and Candida against (CD101) Rezafungin for Analyses Attainment Target Pharmacodynamic theResi Overcoming et S,al. EA, Flanagan JC, Lakota Bader 10.1128/AAC.01627 Adults. in Healthy Echinocandin, V, Ong T, Sandison 1Data. UsingPhase Efficacy (CD101) Rezafungin for Analyses Pharmacokinetic Population CM. S,Rubino V, Flanagan Ong EA,Lakota #P1710. Female Subjects and Male in Healthy F901318 of Formulation Tablet ofanImmediate Multiple Pharmacokinetics J, Dose G,Steiner et al. Allen Kennedy T, #P1711. Vienna, 2017: in volunteers healthy F901318 of pharmacokinetics dose andrepeat the tolerability M, J, Birc G,Steiner Heep Allen Kennedy T, SCY No. (Protocol Subjects Orally toHealthy SCY of Tolerability Safety and the Pharmacokinetic, Evaluate to Study Double 1,Randomized, S.APhase Inc. Subjects Healthy to Infusion Intravenous by Administered APX001 of Pharmacokinetics Hodges Bioavailability onAPX001A Food of theEffect to Investigate and APX001 of OralDoses andMultiple Single of Pharmacokinetics Hodges Pharmacokinet onychomycoses. in agents antifungal Pharmacokineticsof A. D,Coquerel Debruyne Agents Antimicrob Therapy. Combination Antifungal Role of Diego:The San andFusarium, Prolificans Mucorales by Caused Mold Infections etRare al. D, SL,Seidel JD, Reed Jenks Chemother 5 with studies JE.Pharmacological Block ER,Bennett man. and concentration the plasma effects on B:hemodialysis amphotericin and L. Flucytosine RR, Henderson Jr.,MacGregor LG,KleinWJ, JE,Livoti Block ER,Bennett studies. combine injection): complex Blipid (amphotericin profile ABELCET of Pharmacokinetic et CE, al. JF,Swenson Bernardo Adedoyin A, Chemother Agents Antimicrob complex injecti Blipid ofamphotericin study pharmacokinetic al. A LE, et Bolcsak CE, Swenson Adedoyin A, inhumans. deoxycholate excretion TJ. Pharmacokinetics, Walsh DN, DE,LeeJW,Buell RM, Dressler Bekersky I,Fielding illpatients. critically in (Ambisome) Heineman patients. in amphotericinB ofliposomal tolerance and Pharmacokinetics NA,SK. Pandya SH, Kshirsagar Advani Barapatre RJ, PC, Gokhale Ito S. Pharmacokinetics 101. 101. Pharmacokinetics Ito S. Ann Intern Med Intern Ann protected byprotected copyright. All rightsreserved.

MR, Ople E, Shaw KJ, et al. First KJ, et al. MR,Ople E,Shaw and Safety,Tolerability Assess to 1 Phase Study KJ, et al. MR,Ople E,Shaw

Antimicrob Agents Chemother Agents Antimicrob IDWeek , and mass balance of liposomal amphotericin B (AmBisome) and amphotericin B amphotericin and (AmBisome) B amphotericin liposomal massof balance , and n V, Bosse D, Jehn U, et al. Pharmacokinetics of liposomal amphotericin B B amphotericin ofliposomal etal.Pharmacokinetics D,JehnU, Bosse n V,

1972;1: 476 1972;1:

on (Abelcet) in patients with definite or probable systemic fungal infections. infections. systemic fungal probable definite or with inpatients (Abelcet) on 2001;40: 441 2001;40: : San Diego, 2017: abstract #63677. 2017: Diego, San :

2018. Lee J, Thye D. Safety and Pharmacokinetics of CD101 IV, a Novel IV,aNovel ofCD101 and Pharmacokinetics D.Safety J,Thye Lee - 16

1974;80: 613 1974;80:

. -

82.

Antimicrob Agents Chemother Agents Antimicrob

- Paediatr Child Child Health Paediatr 72.

2000;44: 2900 2000;44: Antimicrob Agents Chemother Agents Antimicrob

Antimicrob Agents Chemother Agents Antimicrob - IDWeek Antimicrob Agents Chemother Agents Antimicrob 7.

-

Blind 1997;41: 2201 1997;41: - in - h M. Assessment of the duration of infusion on ofinfusion duration ofthe M. Assessment h Human Study to Assess Safety, Tolerability and Tolerability and Safety, Assess to Study Human : San Diego, 2017: abstract #64127. abstract 2017: Diego, : San - , Cross 078 - 2.

- Antimicrob Agents Chemother Agents Antimicrob 111). 111). d experience from phase I and phase II phase I and fromphase experience d

2011;16: 535 2011;16: - J Antimicrob Chemother Antimicrob J Over, Placebo

- fluorocytosine. fluorocytosine. -

8. data on file data on

2002;46: 828 2002;46: stance Hurdle: Pharmacokinetic Hurdle: stance

2018;62.

2017;61 - 6. -

Controlled, Multiple Controlled,

1997;41: 1275 1997;41: 2018. ECCMID Antimicrob Agents Agents Antimicrob - - 078 Administered Administered 078 33.

clearance. Studies in Studies clearance. ; doi:

1993;32: 133 1993;32: , Lomentospora , Lomentospora : Vienna, 2017: 2017: : Vienna,

2018;62. - 80. Int J Int ECCMID Clin -

Release Release - Dose Dose

- 9. -

: Breakthrough IFI Relapsed IFI Refractory IFI Persistent IFI Term Table1. Summary of Definitions for Invasive Fungal Infection This article is protected by protected is copyright.This article All rightsreserved. Accepted Article

IFI IFI Definition of theof antifungal periodThe symptom timeThe synonym); the spectrum of activity of an antifungal IFI same pathogen at the samesite IFI radiological findings occurring during exposureto anantifungal drug occurring with unchanged from baseline,precede may treatment success.

worsening newor point b of , mycological fi

of breakthrough IFI afterantifungal treatment

evaluated reakthrough

attributableto IFI ndings attributable .

depends on the pharmacokineticproperties or radiologicalor feature;

IFI with or withoutd is the

while treatmenton clinical

discontinuation. IFI is

( first treatment emergentIFI attributable signs or issemination , including fungi

symptoms or . clinical

caused by the

.

sign or is a outside outside Accepted factors Iatrogenic Articlefactors Fungal Factors Host Table2

. Predisposing Factorsfor Breakthrough Invasive Fungal Infections [102 innate and adaptiveimmune responses (e.g., dectin Single nucleotidepolymorphisms within genes encoding proteins for involved in subop for allowing sites “sanctuary” and abscesses), undrained (e.g., control source of Failure Exposure ≥2 antibioticsf Intensive care unit stay receipt of corticosteroid therapy, and other immunosuppressive medications immunosuppression Host norc itrrtto o iaig tde: seset ihu cmaio to comparison without previous Assessment baseline and follow studies: imaging of interpretation Incorrect catheter management bodies foreign Incorrect (e.g., recommended Incorrectintake procedures where (TDM) monitoring intravenous and oral voriconazole, and posaconazole suspensionoral drug therapeutic of of because Absence dosing correct despite levels unpredictable pharmacokinetics drug with high inter tissue and plasma Insufficient Inappropriate selection of antifungals and dosing infectionMixed by Mucormycosis in patient Antifungal exposure can select resistant pathogens causing breakthrough IFI (e.g., Biofilm formation (often incorporating bacterial communities) Outsidethe spectrum of activity Antifungal drug resistance toleranceor antifungal drugs microenvironments iron unfavorable and to hypoxia including adaptation and thermotolerance damage, adh target facilitating traits virulence Fungal - 106]

timal antifungal pharmacokinetics adig r niugl hrp o fna boim o vsua dvcs or devices vascular on biofilms fungal of therapy antifungal or handling [133, 134] [133, [109 bacterial fungal or co - 112]

[135]

[95,98] 97, or or leastat 14 days s receiving voriconazole or echinocandins)

[133, 136 [133, [94 [131, 132] - - up studies - or conditions poor 98]

icuig rsne n drto o neutropenia, of duration and presence including , - 139]

, including , [110,113

- pathogen [96] [99 -

115] - incomplete source control, for examplefor control, source incomplete 101] rne hs dfne vso, tissue evasion, defense host erence, - 17 108] [107,

and i

[124, 125]

- 1 and1 DC ntrapatient variability Tat my e nue by induced be may Traits .

- SIGN, TLR4 and others) [116 - 118] [119

[128] - 123] [129

[126, 127] ]

[130]

-

Ibrexafungerp Fosmanogepix In development Terbinafine Allylamines 5 a Nucleoside lipid complex Amphotericin B, liposomal Amphotericin B, deoxycholate Amphotericin B, Polyenes Voriconazole Posaconazole Itraconazole Isavuconazole Fluconazole Azoles Micafungin Caspofungin Anidulafungin Echinocandins Antifungal Table3 nalog - Flucytosine

s .

Antifungal DrugKey Pharmacokinetic Parameters Classifying Breakthrough IFI

Accepted Article

dose); 10 5 - dose 10 Time to steady s 4 1 without loading dose -

day 7

days

days loading dose) ; 5

i 7 .

1 4 3 4 4 - v days - 14 days14 (without <1 4 days 6 4 ( - - - - - 14 dose 1 1 day 1

. without 2 days2 7 7 5 7 (with loading

with loading

days days

day

days days days days

day

days p.o. )

tate or i.v. or loading

*

Plasma Plasma 80 h 13 4 5 8 6 alf 3 8 27 30 30 24 41 36 24 35 – - - - e 6 - - - 120 11 24 10 limination 20 72 6

-

h

life

h h h h h h h h h

h h

h

h h

h

6 Dosing interval - 8

h ( 24 s formulation) teady State oral

h (tablet,iv ≥ 12 24 24 24 24 24 24 24 24 24 2 12 6 24 4 suspension)

h

h h h h h h h h h h h h

h

after #

Reference [156, 169, 170]169, [156, 163]162, [127, [46, 148 [145, 146][145, 141][140, [175, 176][175, 174][173, 172][171, 165][164, [157 [154 [142 [166 [147] [177] - - - -

168] 161] 156] 144] - 153]

# arefrequently reached on 1.day changefrom the above; steady state isparameter a PK differentfrom drug concentration needed to treatIFI, which loading and maintenancedoses and elimination half-lifeand in particular for antifungalsunder development may Steady* describes state thedynamic equilibrium of overall intake and eliminationand drug, a thus of depends on Rezafungin Olorofim Due to lackof published time-todata steadystate calculated from elimination xhalf-live 4 This article is protected by protected is copyright.This article All rightsreserved.

Accepted Article 1 <1 <1 - 2

days day

20 133 - 30

h

h

168 12

h

h

[183] . . [178, 179][178, [180 - 182]

Figure 1. Treatment Courses of Invasive Fungal Infections

This article is protected by protected is copyright.This article All rightsreserved. Accepted Article

Figure 2 Hachem 2017 End of time End of windowdefined not Begindefined time not of window 2016 Biehl Marks 2011 2010 Wingard window time defin No 2010 Vehreschild neutropenia chemotherapy and by timely toDefined relationship 2012 Hoenigl 2015 Nachbaur 2012 Auberger 2017 Cornely 2014 Lerolle Ananda Ullmann 2007 2007 Cornely exposureprophylaxis by timely toDefined relationship - Rajah 2012

[28]

.

[13]

[23]

[21]

[29] [11] [12] Breakthrough Fungal InfectionsDefinitions Used in Clinical Trials [14] [15]

[24] [26]

Accepted Article

[22]

[25] ed

Day 1 of Day 1 on chemotherapy prophylaxis

Day 3 on prophylaxis

Day 7 on prophylaxis

on

Antifungal Prophylaxis in Hematology

Last day of

neutropenia

Day 1 post prophylaxis

Day 7 post prophylaxis

Day 15 post prophylaxis

Day 30 post prophylaxis