VOLUME 1 NUMBER 1 2007

The Journal of INVASIVE FUNGAL Infections

EDITOR-IN-CHIEF John R Perfect, Durham, NC, USA

Pre-Emptive Therapy in Neutropenic Onco-Hematology Patients Johan Maertens, Koen Theunissen, Katrien Lagrou, Tom Lodewyck, and Johan Van Eldere

Antifungal Prophylaxis in Patients with Hematological Cancers Gloria N Mattiuzzi and Hagop Kantarjian

Case Study: Rhino-Orbito- Cerebral Raoul Herbrecht, Caroline Berthillot, and Cécile Fohrer

www.invasivefungalinfections.com

This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the University of Kentucky College of Medicine and Remedica. The University of Kentucky College of Medicine is accredited by the ACCME to provide continuing medical education for physicians. The University of Kentucky is an equal This journal is supported by an opportunity university. educational grant from Schering-Plough The Journal of Invasive Fungal Infections is supported by an educational grant from Schering-Plough Corporation

Editor-in-Chief Editor John Perfect Zeina A Kanafani Division of Infectious Diseases Director, Research Fellow, Division of Infectious Diseases, Mycology Research Unit, Duke University Duke University Medical Center, Durham, NC, USA Medical Center, Durham, NC, USA

Editorial Advisory Board David Andes Graeme Forrest Assistant Professor, Departments of Medicine Director of Antimicrobial Program at University and Medical Microbiology & , of Maryland and Assistant Director of Infectious University of Wisconsin, Madison, WI, USA Diseases in the Greenebaum Cancer Center Division of Infectious Diseases, University of Maryland Oliver Cornely School of Medicine, Baltimore, MD, USA Klinik I für Innere Medizin, Klinikum der Universität Köln, Köln, Germany Raoul Herbrecht Department of Hematology and Oncology, Ben de Pauw Hôpital de Hautepierre, Strasbourg, France Professor of Medicine, Department of Blood Transfusion Service and Transplant Immunology, Dimitrios P Kontoyiannis University Medical Center St Radboud, Director of Mycology Research Program, Nijmegen, The Netherlands The University of Texas, MD Anderson Cancer Center, Houston, TX, USA Francoise Dromer Head of the Molecular Mycology Unit and Nina Singh Director to the National Reference Center for Associate Professor of Medicine at University Mycoses & , National Reference of Pittsburgh and Chief of Transplant Infectious Center for Mycoses & Antfungals, Institut Diseases, Infectious Diseases Section, VA Medical Pasteur, Paris, France Center, Pittsburgh, PA, USA

Jay Fishman Andrew Ullmann Associate Professor of Medicine, Harvard Klinikum Johannes Gutenberg-Universität, Medical School and Associate Director of MGH Mainz, Germany Transplantation Center, Director of Transplant Infectious Disease and Compromised Host Program, Jo-Anne van Burik Infectious Disease Division, Massachusetts General Department of Medicine, University of Minnesota, Hospital, Boston, MA, USA Minneapolis, MN, USA Foreword Contents

Dear Colleagues, Editorial Welcome to the first issue of The Journal of Invasive Fungal Infections. Antifungal Prophylaxis: to Be or Not to Be, This new, CME-accredited journal has been created to identify and That is Still the Question highlight important developments within the arena of antifungal John R Perfect 2 treatments. The journal will appear quarterly and will provide access to a critical and clinically relevant review of information regarding fungal infections as it pertains to both health and disease. Leading Articles Each issue will include review articles authored by leading specialists. Pre-Emptive Antifungal Therapy in These manuscripts are peer-reviewed for quality and CME-accredited to Neutropenic Onco-Hematology Patients provide an ongoing educational resource. In addition, summaries and analyses of recent papers, chosen for their impact upon the field, are Johan Maertens, Koen Theunissen, provided for the reader together with highlights from recent Katrien Lagrou et al. 4 international conferences. Antifungal Prophylaxis in Patients with The first issue contains two articles and a case study. The first article from Johan Maertens and colleagues (University Hospital Gasthuisberg, Hematological Cancers Catholic University Leuven, Leuven, Belgium) investigates the use of Gloria N Mattiuzzi and Hagop Kantarjian. 10 non-culture based microbiological tools along with more traditional techniques such as assessing clinical signs, cultures, and radiological imaging and emerging methods of detecting fungal antigens DNA to Case Study improve the early diagnosis of invasive fungal infections in patients with Rhino-Orbito-Cerebral Zygomycosis an underlying hematological disorder. It is hoped that starting treatment Raoul Herbrecht, Caroline Berthillot, pre-emptively and using these tools to monitoring the course of fungal disease and response to treatment will improve outcomes in this group. and Cécile Fohrer 17 The second article by Drs Mattiuzzi and Kantarjian (The University of Texas MD Anderson Cancer Center, Houston, TX, USA) explores the use Clinical Reviews of prophylaxis for the treatment of invasive fungal infections. Despite the high rates of morbidity and mortality in patients with hematological 19 malignancies caused by such infections, indiscriminate use of antifungal prophylaxis can lead to high costs, drug toxicity, and the emergence of 21 resistant species. Despite the associated diagnostic difficulties, it is imperative to determine those patients who would benefit most from a 23 prophylactic approach and to ensure that the optimal treatment strategy for the appropriate spectrum of fungal infections is given. Less Common Mycoses 25

The case study, presented by Raoul Herbrecht and coworkers (Hôpital Therapeutics 27 de Hautepierre, Strasbourg, France) examines the treatment course of a patient with rhino-orbito-cerebral zygomycosis. This is followed by a synopsis and critique of recently published scientific findings from several Meeting Report key areas relating to fungal infections. The issue concludes with highlights of presentations from the 46th Annual Interscience Conference on 46th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) conference, held in Antimicrobial Agents and Chemotherapy (ICAAC) San Francisco, CA, earlier this year. San Francisco, CA, USA, September 27–30, 2006 30 We hope you find The Journal of Invasive Fungal Infections an educational and valuable tool. We welcome your feedback regarding the material presented as well as your suggestions for future topics to be covered. On behalf of the Editorial Board and the publisher, I would like to thank you for reading the first issue of what we believe will be an exciting and useful new journal in this developing field. John R Perfect Editor-in-Chief

Editorial Policy Publisher’s Statement The Journal of Invasive Fungal Infections is an independent journal published by Remedica ©2007 Remedica Medical Education and Publishing. All rights reserved. No part of this Medical Education and Publishing. Editorial control is the sole responsibility of the Editor-in-Chief, publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any Editorial Advisory Board, and the Editors. Before publication, all material submitted to the journal means, electronic, mechanical, photocopying, recording, or otherwise without the prior permission is subjected to rigorous review by the Editor-in-Chief, Editorial Advisory Board, Editors, and/or of the copyright owners. While every effort is made by the publishers and editorial board to see independent reviewers for suitability of scientific content, scientific accuracy, scientific quality, and that no inaccurate or misleading data, opinions, or statements appear in this journal, they wish to conflict of interest. make it clear that the material contained in the publication represents a summary of the Aims and Scope independent evaluations and opinions of the authors and contributors. As a consequence, the The Journal of Invasive Fungal Infections is designed to bring a critical analysis of the world fungal board, publishers, and any supporting company accept no responsibility for the consequences of infection literature, written by clinicians, for clinicians, to an international, multidisciplinary audience. any such inaccurate or misleading data or statements. Neither do they endorse the content of the Our mission is to promote better understanding of fungal infections across the global healthcare publication or the use of any drug or device in a way that lies outside its current licensed system by providing an active forum for the discussion of clinical and healthcare policy issues. application in any territory. Leading Articles – These major review articles are chosen to reflect topical clinical and healthcare Editorial Team: Scott Millar, Samantha K Bell Editorial Director: Reghu Venkatesan policy issues in acute coronary syndromes. All contributions undergo a strict editorial review process. Design and artwork: AS&K Skylight Creative Services Publishers: Ian Ackland-Snow, Simon Kirsch Clinical Reviews – The most important papers from the best of the international literature on fungal The Journal of Invasive Fungal Infections (ISSN 1753-3783) is published four times a year. infections are systematically selected by the Editor-in-Chief. The Editors then prepare concise and Additional subscription information is available from the publishers: Remedica Medical Education critical analyses of each paper, and, most importantly, place the findings into clinical context. and Publishing Ltd, Commonwealth House, 1 New Oxford Street, London WC1A 1NU, UK. Meeting Reports – Journal of Invasive Fungal Infections also provides incisive reportage from the Telephone: +44 (0)20 7759 2999 Fax: +44 (0)20 7759 2951 Email: [email protected] most important international congresses. ISSN 1753-3783 EDITORIAL prophylaxis remain. antifungal listed inmyprevious editorial tojustify infection. Despiteachanging medicalworld,thesixcriteria the goalofgettingitjust rightisthedreaded fungal either hastoolittleormuch immunity, andobstructing immune systemwithunprecedented rapidity. Thepatient mixed withimmunemodulators,weare able toalterthe dish”. With monoclonalantibodiesandchemotherapies many patientsare notfarfrom beinga“humanPetri underlying diseasesattheedgeofimmuneprotection, and was adecadeago. of antifungalprophylaxis isasaliveandpertinenttodayit hardware suchasleftventricularassistdevices.Theconcept transplant recipients, andthosewithnewmechanical fungal infectionsinintensivecare units,certainsolidorgan hand, westillstruggletodeveloppreventive strategiesfor leukemia andmyelodysplasticsyndrome. Ontheother receiving inductionchemotherapyfor acutemyeloid graft-versus-host diseaseandinneutropenic patients recent FDAapproval ofposaconazoleprophylaxis during favor ofmore -activeprophylaxis inresponse tothe even inthisriskgroup there islikelytobeafurthershiftin azole prophylaxis isawell-acceptedstrategy. However, in veryhigh-riskbonemarrow transplant recipients, in patientswithpoorimmunereconstitution. Furthermore, recommended iscotrimoxazolefor at present, theonlyantifungalagenttoberoutinely widespread antifungalprophylaxis inHIVinfection and, decade. Forexample,HAART has limitedtheneedfor available. Ofcourse,medicinehasevolvedoverthelast biomarkers andsophisticatedradiographswere notroutinely patients, andpre-emptive treatment strategieswith antifungal drugusewasstandard care infebrileneutropenic antifungal strategies.Itwaswrittenatatimewhenempirical patients were justbeginningtoreceive prophylactic (HAART) forHIVinfection,andhigh-risktransplantation the introduction ofhighlyactiveantiretroviral therapy to Prevent orNot” [1].Thisdiscussionwaswrittenbefore In 1993,Iwrote aneditorialentitled“AntifungalProphylaxis: Duke UniversityMedicalCenter, Durham,NC,USA John RPerfect to Be,ThatisStilltheQuestion Antifungal Prophylaxis: toBeorNot 2 In medicinetoday, weattempt to control severe T HE J UNLOF OURNAL Pneumocystis jiroveci I NVASIVE F UNGAL I not certain. issues. Somepracticesmaybecorrect, but theyare definitely clinical practicebasedonopinions,perceptions, andethical validated usingplacebogroups andare introduced into situations antifungalprophylaxis strategieshavenotbeen blinded designsthatsupportprophylaxis. However, inmany There are someconvincingstudieswithrandomizedand 2. Efficacy defined toxicitiesbutmaybesaferinaerosol forms. candins mustbegivenintravenously. Thepolyeneshave but theydohavesideeffects anddruginteractions,the host. Fortunately, theazolecompoundsare relatively safe, Prophylactic regimens mustnotcausefurtherharmtothe 1. Safety diseases cannotafford tohavetheirspecificallytimed underlying disease.Many of thepatientswithsevere algorithms forthetiming ofthetreatments forthe A fungalinfectioncancause amajor“speedbump”inthe infection issuccessfulcontrol oftheunderlyingdisease. arbitrator inthesuccessfulmanagementofafungal simply makethecaregiver feelbetter?Infact, thefinal allow ustotreat theunderlyingdiseasebetter, ordoesit reduce painandsuffering, improve qualityoflife,and/or really makeadifference inthefinaloutcomeofpatient, criterion forjustificationofantifungalprophylaxis. Doesit In thefinalanalysis,thisremains themost important 4. Consequence infections andtheirprevention toshoweconomicadvantages. need more robust studiesonthepharmacoeconomicsoffungal effective toprevent theseseriousadverseevents.We simply life-threatening fungalinfection,maymeanthatitiscost- and productivity gainbynothavingtomanageorlivewitha reduced hospitalizationsthrough theprevention ofinfections, a smallminoritymayactuallyreceive abenefit.Conversely, acquisition costsfornewdrugsgiventopatients,whenonly It isahospitalexecutive’s nightmare toseethehigh 3. Cost NFECTIONS V OL 1 N O 1 2007 ANTIFUNGAL PROPHYLAXIS

treatments compromised and prevention of a complication of zygomycotic superinfections in patients receiving is critical. , to potential future concerns of breakthrough infections with glabrata and Scedosporiu spp 5. Prevalence during extended-spectrum triazole administration, there is It is always important that each institution understands the always a risk of the increased appearance of resistant risk of fungal infections in their specific high-risk patient and with the widespread use of antifungals. We must populations. Local epidemiology is important. I previously take care to keep our limited number of antifungal agents suggested that the risk group for prophylaxis would need a intact for treatment strategies. 10% frequency of fungal infection to make any single In my previous editorial I stated an opinion that is as true institution observe a statistical improvement in terms of today as it was in the 1990s: “An ounce of prevention is a reduction of infections with a prophylaxis strategy [1]. worth a pound of cure is only true when you know the true This figure is still a reasonable starting point, but with large weight of the prevention”. We must be rigorous in our numbers of high-risk patients in certain centers, prophylaxis clinical practice and supporting studies to ensure that may be successfully used when the frequency is even a little antifungal prophylaxis validates its use in specific patient lower than 10%. populations using consideration of the six criteria set out above. When the balance of information supports antifungal 6. Resistance prophylaxis we should not be afraid to use it. On the other When we unleash a widespread use of an antimicrobial hand, we should not blindly accept its existence. Taken agent, we need to be aware of the potential for drug together, I would always prefer to prevent a fungal infection resistance development. Fortunately, fungi do not possess than treat it, and I suspect the patient and the attending drug-resistance plasmids or transposons, although drug clinician concur with this statement. efflux pumps can upregulate within a strain to make the agent ineffective, and superinfections with drug-resistant Reference fungi have been well-described. From the recent occurrence 1. Perfect JR. Antifungal prophylaxis: to prevent or not. Am J Med 1993;94:233–4.

THE JOURNAL OF INVASIVE FUNGAL INFECTIONS VOL 1 NO 1 2007 3 LEADING ARTICLE Email: [email protected] Cell Transplantation Unit,Herestraat 49,B-3000Leuven, Belgium. Department ofHematology, AcuteLeukemiaand HematopoieticStem Address forreprints: JohanMaertens,UniversityHospitalGasthuisberg, of MedicalMicrobiology, UniversityHospitalGasthuisberg, CatholicUniversityLeuven,Belgium and JohanvanEldere J InvasiveFungalInfect starting antifungaltherapypre-emptivelyandformonitoringthecourseoffungaldiseaseresponseto treatment. and especiallyradiologicalimaging,theymayproveusefulinscreeningpatientswithhematologicalmalignancies, bothfor useful whenusedasscreeningtoolsovertheperiodofhighestrisk.Together withassessmentofclinicalsigns,cultures, available andemergingmethodstodetectfungalantigenssophisticatedtechniquesDNA maybe administered early. Non-culturebasedmicrobiologicaltoolsareattheforefrontofthisparadigm shift.Commercially empirical therapytoscreeninghigh-riskadultneutropenicpatientssothatappropriateantifungalcanbe empirical useofantifungalagents.Currently, thereisashiftinemphasisfromwaitingfordefinitediagnosisorstarting hampered bytheinabilitytomakeanearlydiagnosis.Therefore,mostpractitionersrelyongeneralizedprophylaxisand/or The managementofinvasivefungal(mold)infectionsinpatientswithanunderlyinghematologicaldisorderhasbeen 1 Johan Maertens Neutropenic Onco-HematologyPatients Pre-Emptive AntifungalTherapyin spectrum antibacterialcoverageusuallyrepresents thefirst infection. Fevernotresponding to4–5days ofbroad- usually non-specific,maynotmanifestintheearlystages of responses andclinicalfeatures that,althoughvariableand many high-riskpatientshavedecreased inflammatory substantial delaysinestablishingadiagnosis[5].Indeed, (>70% forsomemoldinfections)stem,inpart,from to potentiallycurativecytoreductive therapy[4]. immunosuppression, oftenresulting inunacceptabledelays a highpropensity toreactivate inthesettingofcontinued Moreover, eveniftreated successfully, fungalinfectionshave syndrome whoundergo intensivechemotherapy[2,3]. in patientswithacuteleukemiaormyelodysplastic hematopoietic stemcelltransplant(HSCT)recipients and attributable mortalityrates,especiallyinallogeneic In addition,thesefungalinfectionscarryhighcrudeand all severely immunosuppressed hematologypatients[1]. continue tobeanemerging causeofmorbidityinvirtually infections (angio-invasivepulmonaryaspergillosis inparticular) incidence ofinvasiveyeastinfections,fungal(mold) While antifungalprophylaxis hassuccessfullydecreased the 4 Department ofHematology, AcuteLeukemiaandHematopoieticStemCellTransplantation Unit, The highmortalityratesofinvasivefungalinfections 1 2007; , KoenTheunissen 1 (1):4–9. T 2 HE J UNLOF OURNAL I NVASIVE 1 , KatrienLagrou F UNGAL I overtreatment, resulting inincreased expenditure andriskof empirical antifungaltherapy isassociatedwithsignificant relapsing fever fordiagnosingfungalinfections.Consequently, the lowspecificityandpredictive valueofpersistentor However, the late1990switnessedagrowing awareness of repeatedly beenendorsedbyconsensusguidelines[10]. been adoptedasthestandard ofcare worldwideandhas two smallseriesofpatients[8,9],thisstrategyhasrapidly antifungal therapyinthissettinghasbeenassessed just fungal infection.Althoughtheeffectiveness ofempirical clinical, microbiological, orradiologicalfindingssuggestiveof unexplained orrelapsing feverintheabsence ofother following conventionalintensityconditioning)with leukemia ormyelodysplasticsyndrome andallogeneicHSCT neutropenic patients(intensivechemotherapyforacute [7]. Empiricalantifungaltherapyprimarilytargets profoundly use ofantifungalagentswasintroduced inthelate1980s effort toovercome thesediagnosticobstacles,theempirical because theyare insensitiveandtimeconsuming.Inan these toolshadalimitedimpactonclinicaldecisionmaking were thecornerstonesoffungalinfectiondiagnosis,but and microscopy), histological,andradiologicaltechniques fungal burden islowandtissuedamagelimited[6]. early initiationofadequateantifungaltherapy, whenthe However, survivalratescanbedramaticallyimproved bythe clinical clueinnon-steroid treated neutropenic patients[5]. NFECTIONS For manyyears,conventionalmicrobiological (culture V 2 OL , Tom Lodewyck 1 N O 1 2007 1 , 2 Department PRE-EMPTIVE ANTIFUNGAL THERAPY IN NEUTROPENIC ONCO-HEMATOLOGY PATIENTS

adverse effects [11]. In addition, most empirical studies incorporation of new, non-invasive, non-culture based continue to observe an approximately 10% incidence of microbiological tools (NCBMTs). breakthrough fungal infection [12]. Recent improvements in the diagnosis of fungal infections New diagnostic tools from the mycology lab have prompted a further reappraisal of the concept of Detection of galactofuranosyl-containing molecules empirical antifungal therapy [13]. The time period between Over the past 2 decades, significant experience has been the biological start of the infection and the appearance of gained with the PA-EIA, a second-generation seroassay with clinical (e.g. pleuritic chest pain or improved performance compared with the earlier latex hemoptysis) represents a window of opportunity that may agglutination assay. This sandwich enzyme immunoassay allow earlier and more targeted therapeutic intervention. detects galactofuranosyl-containing molecules, including In such a scenario, the decision to start antifungal therapy galactomannan (GM) – a polysaccharide cell wall component would not be triggered by fever but would rely both on of spp (and a few other molds) that is released better identification of those at risk and the availability of into the circulation during hyphal growth in tissues [19]. sensitive techniques able to facilitate rapid and early The test has been commercially available in Europe since the diagnosis of invasive fungal infections. This window could be mid 1990s and was approved by the US Food and Drug identified via prospective screening strategies using new Administration (FDA) for diagnostic use in May, 2003 [20]. serodiagnostic assays – the Platelia Aspergillus enzyme Consensus criteria from the EORTC/MSG (European immunoassay (PA-EIA, Bio-Rad Laboratories, Marnes-La- Organisation for the Research and Treatment of Cancer and Coquette, France & Bio-Rad Laboratories, Hercules, CA, the Study Group) state that the detection of GM USA) for the detection of galactomannan (GM), or the in the body fluids (predominantly serum/plasma and Fungitell assay, (Associates of Cape Cod Inc., East Falmout, bronchoalveolar lavage [BAL] fluid) of cancer patients and MA, USA) for the detection of (1,3)-β-D-glucan – and/or HSCT recipients is as diagnostically valuable as the isolation polymerase chain reaction (PCR) techniques for the detection of Aspergillus spp on culture or the microscopic of fungal-specific DNA [14]. In line with recent guidelines, demonstration of hyphae [21]. GM detection in serum and these tools should be used in conjunction with modern BAL fluid was included in the microbiological criteria imaging techniques such as high-resolution computed following the excellent diagnostic accuracy of the PA-EIA as tomography (CT) scanning, which has been shown to reported by studies in the late 1990s involving profoundly improve earlier diagnosis and survival [15,16]. neutropenic patients undergoing chemotherapy for acute In the most recent literature, this new approach is usually leukemia/myelodysplastic syndrome or recipients of HSCT referred to as “pre-emptive antifungal therapy”, although [22–28]. In some of these studies, PA-EIA positivity “targeted prophylaxis”, “early targeted therapy”, “presumptive preceded the conventional diagnosis of invasive aspergillosis therapy”, and even “targeted empirical therapy” have all (IA) by an average of 1 week [29]. However, more recent been used to describe the same technique. Conceptually, studies that have included non-neutropenic patients pre-emptive therapy involves the treatment of those patients (e.g. solid tumor patients, solid organ transplant recipients, in whom there is evidence of the presence of a and intensive care unit patients) have reported significantly that predisposes for the development of invasive disease. lower sensitivities and positive predictive values [19]. The concept has successfully been applied to the management Hence, it remains unclear whether a case of IA can be of viral infections following HSCT or solid organ transplantation. defined by the PA-EIA and, more importantly, whether a Indeed, transplant recipients with suspected cytomegalovirus reliable pre-emptive approach can be designed based upon (e.g. positive antigenemia or PCR assay) often receive pre- serial monitoring for the presence of GM [30]. emptive antiviral therapy in view of their increased likelihood A recent meta-analysis of 27 studies assessed the diagnostic of developing life-threatening disease if left untreated [17]. performance of the PA-EIA and reported a pooled sensitivity However, the new serological assays for fungal diagnosis do (for proven and probable cases of IA) of 61% and an overall not allow this form of pre-emptive approach, since specificity of 93% [31]. However, the study also identified seropositivity signifies that the patient already has fungal subgroups of patients and conditions in which the assay disease. A truly pre-emptive antifungal approach, similar to performed significantly better: the accuracy of the test the antiviral strategy, is not yet feasible, although PCR-based differed by study population (adults > children), by underlying attempts look promising [18]. Nevertheless, for the purpose disorder (hematological malignancy and allogeneic stem cell of this article and to be consistent with recent literature, we transplantation > solid organ transplantation), and by the will use the term “pre-emptive antifungal therapy” to stringency of the criteria used to define a case of IA describe an antifungal approach that is based on the (EORTC/MSG criteria > other criteria). Thus, methodological

THE JOURNAL OF INVASIVE FUNGAL INFECTIONS VOL 1 NO 1 2007 5 JOHAN MAERTENS, KOEN THEUNISSEN, KATRIEN LAGROU ET AL

and clinical inter-study heterogeneities undermine the have hampered the evaluation of the GM detection assay generalizability of test results across patient populations also apply to the detection of (1,3)-β-D-glucan. These [30,32]. For instance, differences in the pathogenesis of IA include the inadequate use of a case–control design, the in neutropenic and steroid-treated patients account in part heterogeneity of the study population, the spectrum of for variations in test performance [33,34]. alternative diagnoses, the number of collected serum In addition, a number of clinically important caveats samples, and the cut-off for positivity [42,43]. In addition, remain regarding the performance of the PA-EIA, including the use of endotoxin- and glucan-free glassware is required the negative impact of mold-active antifungal prophylaxis or and a number of factors can lead to false-positive readings, empirical therapy [35,36]. Other factors, such as the use of including the use of albumin or immunoglobulins, exposure antibacterial therapy with semi-synthetic β-lactam antibiotics to glucan-containing gauze (following ), and (piperacillin-tazobactam; amoxicillin-clavulanate) [37] or the hemodialysis [14]. Moreover, the assay cross-reacts with presence of anti-GM , may also affect the some antimicrobial preparations, both in vitro and in vivo performance and/or interpretation of the assay [28]. (amoxicillin-clavulanate) and can test false-positive in Fortunately, one area of controversy has recently been patients with Gram-positive bacteremia [44,45]. resolved; in Europe, the optical density index cut-off level for However, given the broad spectrum of fungal species a positive result has been lowered to 0.5, identical to the that can be detected by the assay and the excellent negative proposed cut-off in the US [38]. However, different cut-off predictive value, these tests seem to be useful for excluding values may be needed for different clinical settings [39]. invasive fungal infections. The specificity and the positive Finally, the optimal frequency of sampling has not yet been predictive value of the glucan assay could be improved by determined and it remains unclear whether or not a positive combining it with the PA-EIA. sample should be confirmed and, if so, whether this should be by a subsequent sample or by retesting the first sample Detection of fungal DNA [40]. However, overall, the high specificity and excellent The amplification of unique gene sequences by polymerase negative predictive value of the PA-EIA in neutropenic chain reaction (PCR) techniques offers the potential for rapid patients, especially if used in combination with sensitive detection and identification of molds at the genus level radiological tools, allows a diagnosis of IA to be ruled out. [46,47]. Mainly in European centers, PCR detection is increasingly appreciated as being a valuable diagnostic tool Detection of (1,3)-β-D-glucan for diagnosing fungal infections. Sensitivity and negative Glucans, (1,3)-β-D-linked polymers of glucose, are part of predictive values have usually been excellent. However, the outer cell wall of most pathogenic yeasts and there remains a great deal of debate regarding routine filamentous fungi (exceptions are Cryptococcus spp and the clinical applicability. All PCR assays have been developed zygomycetes). Two commercially available colorimetric assays in-house, using different sample specimens, extraction (Fungitell [previously Glucatell]), and FungiTec G, Seikagaku methods, PCR designs, and detection and specification of Kogyo Corporation, Tokyo, Japan) and one turbidimetric the amplicon. Thus, due to the lack of a standardized, assay (Wako-WB003, Wako Pure Chemical industries, reproducible, and validated (commercially available) method, Osaka, Japan) can be used to detect (1,3)-β-D-glucan. the routine use of PCR in the diagnosis of invasive fungal These assays are based on the ability of horseshoe crab infections cannot yet be recommended. However, panfungal hemolymph to clot in response to trace amounts of assays that amplify a conserved region of 18S ribosomal (1,3)-β-D-glucan (as low as 1 pg/mL) [5,14]. DNA, using real-time techniques combined with automated These tests are widely used in Japan and the Fungitell DNA extraction, may allow standardization and assay has recently been approved by the FDA as an aid for reproducibility between centers and thus broaden the clinical the diagnosis of invasive fungal infections in cancer patients, applicability of PCR-based diagnosis in the near future. based on an assessment in patients with acute leukemia and Once again, PCR may be useful for excluding invasive myelodysplastic syndrome [41]. At a cut-off level 60 pg/mL, fungal infections because of its ability to detect a broad the negative predictive value of twice weekly sampling was spectrum of fungi and its high negative predictive value. 100%. Additionally, sensitivity was 100% if one positive assay was considered a truly positive result. Of note, test Combination of non-culture based tools results were not influenced by the prophylactic or empirical Prior to 2002, only a few small retrospective studies use of antifungals. investigated the use of combinations of NCBMTs for the However, overall experience with these assays remains diagnosis of fungal infection, with generally inconsistent limited and many of the methodological shortcomings that results. More recently, Buchheidt and colleagues compared

6 THE JOURNAL OF INVASIVE FUNGAL INFECTIONS VOL 1 NO 1 2007 PRE-EMPTIVE ANTIFUNGAL THERAPY IN NEUTROPENIC ONCO-HEMATOLOGY PATIENTS

LightCycler PCR (Roche, Basel, Switzerland), nested PCR, episodes, 22 were confirmed by positive culture; culture- and PA-EIA in a series of hematology patients [48]. Nested negative, PCR-positive episodes were mainly seen in patients PCR was superior to PA-EIA with respect to sensitivity with hepatosplenic candidiasis. Of note, PCR-positivity (63.6% vs. 33.3%), but significantly more episodes tested preceded the final blood culture by 1–8 days, resulting in false-positive by PCR. In addition, the rate of false-positivity earlier adequate therapy. correlated with the total number of samples per study Recently, we assessed the feasibility of a computed episode. In line with previous observations, real-time tomography (CT) scan combined with a GM detection- quantitative LightCycler PCR was less sensitive. A Japanese based approach (with an optical density cutoff level of ≥0.5) group monitored the levels of Aspergillus DNA, GM, and in a prospective trial in adult neutropenic hematology (1,3)-β-D-glucan (by kinetic assay) in high-risk hematology patients [55]. This non-comparative study was designed to patients and evaluated the diagnostic potentials by using explore the feasibility of starting antifungal therapy based receiver operating characteristic (ROC) analyses [49]. on diagnostic information with a high predictive value (both The ROC curve for the PA-EIA (at an optical density index positive and negative) as an alternative to the classic of 0.6) was better than that for the other two tests. empirical approach, in an attempt to reduce the exposure to Recent studies that focused on combinations of these tests antifungal agents. Whereas a purely fever-driven approach demonstrated improved performance with GM plus would have resulted in antifungal treatment in at least 41 (1,3)-β-D-glucan detection [50], GM plus PCR detection of 136 episodes (30%), a pre-emptive algorithm led to [51], and PCR enzyme-linked immunosorbent assay plus initiation of antifungals in <25% of these episodes. GM detection [52]. Furthermore, this approach identified 10 episodes of fungal infection that would not have been identified by the The pre-emptive approach conventional approach due to the absence of fever or the The excellent negative predictive value of the PA-EIA, PCR, presence of coexisting febrile conditions. Just one case of or (1,3)-β-D-glucan assay should convince clinicians to disseminated zygomycosis out of 22 cases of invasive fungal withhold empirical antifungal therapy in persistently febrile infection remained undetected. The overall mortality rate of neutropenic patients with no other clinical, microbiological, 18% was considered acceptable for a neutropenic or radiological evidence of fungal infection. Conversely, population with probable invasive fungal disease. These given the high positive predictive value in neutropenic encouraging data have been confirmed by a study in patients, confirmed test positivity should trigger a diagnostic allogeneic HSCT recipients [56] and by two recent Spanish work-up and should lead to the early pre-emptive initiation series [57,58]. of antifungal (anti-Aspergillus in the case of PA-EIA There are now several microbiological and radiological positivity) therapy, irrespective of the presence or absence of tools that have the potential to be used to identify an fever. Hence, the pre-emptive use of antifungals may invasive fungal/Aspergillus infection at an early stage or that precede or follow the classic criterion for starting empirical can rule out the presence of an invasive fungal/Aspergillus antifungal therapy. This reasoning is supported by a decision infection in high-risk neutropenic hemato-oncology patients. analysis model presented by Severens et al., in which pre- The high negative predictive value of a normal CT scan and emptive therapy, in contrast to a conventional approach, serial negative NCBMTs rules out the presence of an invasive resulted in fewer patients being treated without incorrectly pulmonary fungal infection, whereas the high positive withholding therapy [53]. predictive value of a suggestive CT scan (e.g. halo-sign) and However, thus far, few studies have assessed the so-called positive NCBMTs warrants the initiation of mold-active pre-emptive approach. One study looked at the feasibility antifungal therapy (the agent of choice depends on the of a PCR-guided strategy in pediatric cancer patients who species specificity of the assay). All scenarios in-between did not receive antifungal prophylaxis [54]. Patients with remain inconclusive (fungal or non-fungal; infectious or neutropenic fever were screened for fungal infection by non-infectious) and warrant a more aggressive approach, means of blood culture and PCR assay simultaneously. including invasive diagnostic procedures for adequate Antifungal therapy was withheld if PCR and blood culture sampling for culture and microscopy (e.g. CT-guided results remained negative and if there was no other evidence bronchoscopy with lavage) and for obtaining tissue of invasive fungal infection. Conversely, positive blood specimens for histopathological examination [59]. culture or two consecutive positive PCR assays resulted in Prospective multicenter studies comparing pre-emptive initiation of antifungal treatment. Antifungal therapy was or early therapy approaches versus empirical therapy should not administered in 52 PCR-negative episodes and fungal determine the impact of more targeted approaches in terms infection was not documented. Of 29 PCR-positive of outcome and cost-effectiveness [60]. However, as recently

THE JOURNAL OF INVASIVE FUNGAL INFECTIONS VOL 1 NO 1 2007 7 JOHAN MAERTENS, KOEN THEUNISSEN, KATRIEN LAGROU ET AL

evidenced, these studies will be difficult to undertake 7. Martino R, Viscoli C. Empirical antifungal therapy in patients with neutropenia and because they require the full cooperation and compliance of persistent or recurrent fever of unknown origin. Br J Haematol 2005;132:138–54. 8. Pizzo PA, Robichaud KJ, Gill FA et al. Empiric antibiotic and antifungal therapy for cancer all parties (clinicians, microbiologists, radiologists, nursing patients with prolonged fever and granulocytopenia. Am J Med 1982;72:101–11. team etc.) and the strict adherence to a protocol of 9. EORTC International Antimicrobial Therapy Cooperative Group. Empiric antifungal therapy in febrile granulocytopenic patients. Am J Med 1989;86:668–72. minimum standards of diagnosis [61]. Such endeavors will 10. Böhme A, Runcke M, Buchheidt D et al. Treatment of fungal infections in hematology only be possible if healthcare providers combine their efforts and oncology – guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO). Ann Hematol 2003;82:S133–40. and establish a consortium to support such a study using 11. De Pauw B. Between over- and undertreatment of invasive fungal disease. Clin Infect Dis a standardized diagnostic approach that has gained 2005;41:1251–3. 12. Klastersky J. Antifungal therapy in patients with fever and neutropenia – more rational widespread acceptance [62]. and less empirical? N Engl J Med 2004;351:1445–7. 13. Verweij P. Advances in diagnostic testing. Med Mycol 2005;43(Suppl 1):S121–4. Conclusion 14. Quindós G. New microbiological techniques for the diagnosis of invasive mycoses caused by filamentous fungi. Clin Microbiol Infect 2006;12(Suppl 7):40–52. The management of invasive fungal (mold) infections 15. Caillot D, Casasnovas O, Bernard A et al. Improved management of invasive pulmonary in patients with an underlying hematological disorder has aspergillosis in neutropenic patients using early thoracic computed tomographic scan and surgery. J Clin Oncol 1997;5:139–47. been hampered by the inability to diagnose these infections 16. Denning DW, Kibbler CC, Barnes RA; British Society for Medical Mycology. British Society since definite diagnosis invariably centers on histological for Medical Mycology proposed standards of care for patients with invasive fungal infections. Lancet Infect Dis 2003;3:230–40. identification of hyphae in tissue or on culture. As such, most 17. Baillie GM. Prevention of cytomegalovirus disease in solid organ transplant patients: practitioners tend to rely on generalized prophylaxis and prophylactic versus preemptive therapy. Am J Health Syst Pharm 2006;63:S10–6. 18. Einsele H, Quabeck K, Muller KD et al. Prediction of invasive pulmonary aspergillosis empirical therapy. Currently, there is a shift in emphasis from from colonisation of lower respiratory tract before marrow transplantation. waiting for definite diagnosis or starting empirical therapy Lancet 1998;352:1443. 19. Mennink-Kersten M, Donnelly J, Verweij P. Detection of circulating galactomannan for the to screening high-risk adult neutropenic patients so that diagnosis and management of invasive aspergillosis. Lancet Infect Dis 2004;4:349–57. clinicians can administer appropriate antifungal therapy early, 20. Wheat L. Galactomannan antigen detection for diagnosis of invasive aspergillosis, Part I. Clin Microbiol Newsletter 2005;27:52–8. when it can potentially improve patient outcome. NCBMTs 21. Ascioglu S, Rex J, de Pauw B et al. Defining opportunistic invasive fungal infections in are at the forefront of this paradigm shift. Commercially immunocompromised patients with cancer and hematopoietic stem cell transplants: an international consensus. Clin Infect Dis 2002;34:7–14. available and emerging methods to detect fungal antigens 22. Rohrlich P, Sarfati J, Mariani P et al. Prospective sandwich enzyme-linked immunosorbent and sophisticated techniques to detect fungal DNA may be assay for serum galactomannan: early predictive value and clinical use in invasive aspergillosis. Pediatr Infect Dis 1996;15:232–7. useful when used serially over the period of highest risk. 23. Bretagne S, Costa JM, Bart-Delabesse E et al. Comparison of serum galactomannan Together with the assessment of clinical signs, cultures, and antigen detection and competitive polymerase chain reaction for diagnosing invasive aspergillosis. Clin Infect Dis 1998;26:1407–12. radiological imaging (CT scan), they may prove useful in 24. Maertens J, Verhaegen J, Demuynck H et al. Autopsy-controlled prospective evaluation screening patients with hematological malignancies, both for of serial screening for circulating galactomannan by a sandwich enzyme-linked immunosorbent assay for hematological patients at risk for invasive aspergillosis. starting antifungal therapy and for monitoring the course of J Clin Microbiol 1999;37:3223–8. the disease and the response to treatment. 25. Ulusakarya A, Chachaty E, Vantelon JM et al. Surveillance of Aspergillus galactomannan antigenemia for invasive aspergillosis by enzyme-linked immunosorbent assay in neutropenic patients treated for hematological malignancies. Hematol J 2000;1:111–6. Disclosure 26. Maertens J, Verhaegen J, Lagrou K et al. Screening for circulating galactomannan as a noninvasive diagnostic tool for invasive aspergillosis in prolonged neutropenic patients J Maertens is a member of the advisory boards for Gilead, and stem cell transplantation recipients: a prospective validation. Blood 2001;97:1604–10. MSD, Shering-Plough, Zeneus, Pfizer, and Astellas, and has 27. Sulahian A, Boutboul F, Ribaud P et al. Value of antigen detection using an enzyme immunoassay in the diagnosis and prediction of invasive aspergillosis in two adult and received speakers’ honoraria from all of these companies. pediatric hematology units during a 4-year prospective study. Cancer 2001;91:311–8. K Theunissen, K Lagrou, T Lodewyck, J van Eldere have no 28. Herbrecht R, Letscher-Bru V, Oprea C et al. Aspergillus galactomannan detection in the diagnosis of invasive aspergillosis in cancer patients. J Clin Oncol 2002;20:1898–906. relevant financial interests to disclose. 29. Maertens J, Van Eldere J, Verhaegen J et al. Use of circulating galactomannan screening for early diagnosis of invasive aspergillosis in allogeneic stem cell transplant recipients. J Infect Dis 2002;186:1297–306. References 30. Maertens J, Theunissen K, Deeren D et al. Defining a case of invasive aspergillosis by serum galactomannan. Med Mycol 2006;44(Suppl):173–8. 1. Pagano L, Caira M, Candoni A et al. The epidemiology of fungal infections in patients with hematologic malignancies: the SEIFEM-2004 study. Haematologica 2006;91:1068–75. 31. Pfeiffer C, Fine J, Safdar N. Diagnosis of invasive aspergillosis using a galactomannan assay: a meta-analysis. Clin Infect Dis 2005;42:1417–27. 2. Cordonnier C, Maury S, Ribaud P et al. A grading system based on severity of infection to predict mortality in allogeneic stem cell transplant recipients. Transplantation 2006;82:86–92. 32. Whiting P, Rutjes AWS, Reitsma JB et al. Sources of variation and bias in studies of diagnostic accuracy. A systematic review. Ann Intern Med 2004;140:189–202. 3. Herbrecht R, Moghadamm A, Mahmal L et al. Invasive aspergillosis in the hematologic and immunologic patient: new findings and key questions in leukemia. Med Mycol 33. Stephens-Romero S, Mednick A, Feldmesser M. The pathogenesis of fatal outcome 2005;43(Suppl 1):S239–49. in murine pulmonary aspergillosis depends on the neutrophil depletion strategy. Infect Immun 2005;73:114–25. 4. Martino R, Parody R, Fukuda T et al. Impact of the intensity of the pre-transplant conditioning regimen in patients with prior invasive aspergillosis undergoing allogeneic 34. Balloy V, Huerre M, Latgé J, Chignard M. Differences in patters of infection and hematopoietic stem cell transplantation: a retrospective survey of the infectious diseases inflammation for corticosteroid treatment and chemotherapy in experimental invasive working party of the European Group for Blood and Marrow Transplantation. pulmonary aspergillosis. Infect Immun 2005;73:494–503. Blood 2006;108:2928–36. 35. Marr K, Balajee S, McLaughlin L et al. Detection of galactomannan antigenemia by 5. Hope W, Walsh T, Denning D. Laboratory diagnosis of invasive aspergillosis. Lancet Infect enzyme immunoassay for the diagnosis of invasive aspergillosis: variables that affect Dis 2005;5:609–22. performance. J Infect Dis 2004;190:641–9. 6. von Eiff M, Roos N, Schulten R et al. Pulmonary aspergillosis: early diagnosis improves 36. Marr K, Laverdiere M, Gugel A, Leisenring W. Antifungal therapy decreases sensitivity survival. Respiration 1995;62:341–7. of the Aspergillus galactomannan enzyme immunoassay. Clin Infect Dis 2005;40:1762–9.

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37. Aubry A, Porcher R, Bottero J et al. Occurrence and kinetics of false-positive Aspergillus 51. Millon L, Piarroux R, Deconinck E et al. Use of real-time PCR to process the first galactomannan test results following treatment with β-lactam antibiotics in patients with galactomannan-positive serum sample in diagnosing invasive aspergillosis. J Clin Microbiol hematological disorders. J Clin Microbiol 2006;44:389–94. 2005;43:5097–101. 38. Maertens J, Theunissen K, Verbeken E et al. Prospective clinical evaluation of lower cut- 52. Florent M, Katsahian S, Vekhoff A et al. Prospective evaluation of a polymerase chain offs for galactomannan detection in adult neutropenic cancer patients and haematological reaction-ELISA targeted to Aspergillus fumigatus and Aspergillus flavus for the early stem cell transplant recipients. Br J Haematol 2004;126:852–60. diagnosis of invasive aspergillosis in patients with hematological malignancies. 39. Cordonnier C, Botterel F, Pautas C et al. Galactomannan antigenaemia has a higher J Infect Dis 2006;193:741–7. diagnostic yield in invasive aspergillosis in deeply neutropenic patients than in others [Abstract]. Bone Marrow Transplant 2006;37(Suppl 1):P674. 53. Severens Jl, Donnelly JP, Meis JF et al. Two strategies for managing invasive aspergillosis: a decision analysis. Clin Infect Dis 1997;25:1148–54. 40. Rex J. Galactomannan and the diagnosis of invasive aspergillosis. Clin Infect Dis 2006;42:1428–30. 54. Lin M, Lu H, Chen W. Improving efficacy of antifungal therapy by polymerase chain 41. Odabasi Z, Mattiuzzi G, Estey E et al. Beta-D-glucan as a diagnostic adjunct for invasive reaction-based strategy among febrile patients with neutropenia and cancer. Clin Infect fungal infections: validation, cutoff, development, and performance in patients with acute Dis 2001;33:1621–7. myelogenous leukemia and myelodysplastic syndrome. Clin Infect Dis 2004;39:199–205. 55. Maertens J, Theunissen K, Verhoef G et al. Galactomannan and computed tomography- 42. Ostrosky-Zeichner L, Alexander B, Kett D et al. Multicenter clinical evaluation of the based pre-emptive antifungal therapy in neutropenic patients at high risk for invasive (1–>3) β-D-glucan assay as an aid to diagnosis of fungal infections in humans. Clin Infect fungal infection: a prospective feasibility study. Clin Infect Dis 2005;41:1242–50. Dis 2005;41:654–9. 56. Busca A, Locatelli F, Barbui A et al. Usefulness of sequential Aspergillus galactomannan β 43. Upton A, Leisenring W, Marr K. (1->3) -D-glucan assay in the diagnosis of invasive fungal antigen detection combined with early radiologic evaluation for diagnosis of invasive Clin Infect Dis 42 infections. 2006; :1054–6. pulmonary aspergillosis in patients undergoing allogeneic stem cell transplantation. 44. Mennink-Kersten M, Warris A, Verweij P. 1,3- β-D-glucan in patients receiving intravenous Transplant Proc 2006;38:1610–3. amoxicillin-clavulanic acid. N Engl J Med 2006;354:2834–5. 57. Aguilar-Guisado M, Cisneros J, Cordero E et al. Empirical antifungal therapy for persistent β 45. Pickering J, Sant H, Bowles C et al. Evaluation of a (1->3) -D-glucan assay for diagnosis febrile neutropenia in selected patients [Abstract M-898]. Presented at The 46th of invasive fungal infections. J Clin Microbiol 2005;43:5957–62. Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, 46. Buchheidt D, Hummel M. Aspergillus polymerase chain reaction (PCR) diagnosis. CA, USA, September 27–30, 2006. Med Mycol 2005;43(Suppl 1):S139–45. 58. Diaz-Pedroche C, Aguado J, Lizasoain M et al. Proposal for a new strategy of antifungal 47. Donnelly J. Polymerase chain reaction for diagnosing invasive aspergillosis: getting closer prophylaxis and early treatment of invasive aspergillosis in neutropenic patients [Abstract but still a ways to go. Clin Infect Dis 2006;42:487–9. M-910]. Presented at The 46th Interscience Conference on Antimicrobial Agents and 48. Buchheidt D, Hummel M, Schleiermacher D et al. Prospective clinical evaluation of Chemotherapy, San Francisco, CA, USA, September 27–30, 2006. a LightCycler-mediated polymerase chain reaction assay, a nested-PCR assay and a galactomannan enzyme-linked immunosorbent assay for detection of invasive aspergillosis 59. Maertens J, Deeren D, Dierickx D, Theunissen K. Preemptive antifungal therapy: still in neutropenic cancer patients and haematological stem cell transplant recipients. a way to go. Curr Opin Infect Dis 2006;19:551–6. Br J Haematol 2004;125:196–202. 60. Wheat L. Galactomannan antigen detection for diagnosis of invasive aspergillosis. Part II. 49. Kawazu M, Kanda Y, Nannya Y et al. Prospective comparison of the diagnostic potential of Clin Microbiol Newsletter 2005;27:59–63. real-time PCR, double-sandwich enzyme-linked immunosorbent assay for galactomannan, 61. White P, Linton C, Perry M et al. The evolution and evaluation of a whole blood and a (1,3)-β-D-glucan test in weekly screening for invasive aspergillosis in patients with polymerase chain reaction assay for the detection of invasive aspergillosis in haematology hematological disorders. J Clin Microbiol 2004;42:2733–41. patients in a routine clinical setting. Clin Infect Dis 2006;42:479–86. 50. Pazos C, Ponton J, del Palacio A. Contribution of (1→3)- β-D-glucan chromogenic assay to diagnosis and therapeutic monitoring of invasive aspergillosis in neutropenic adult patients: 62. White P, Barton R, Guiver M et al. A consensus on fungal polymerase chain reaction a comparison with serial screening for circulating galactomannan. J Clin Microbiol diagnosis? A United Kingdom–Ireland evaluation of polymerase chain reaction methods 2005;43:299–305. for detection of systemic fungal infections. J Mol Diagn 2006;8:376–84.

THE JOURNAL OF INVASIVE FUNGAL INFECTIONS VOL 1 NO 1 2007 9 LEADING ARTICLE Email: [email protected]. Boulevard, Box428,Houston,TX77030,USA. MD AndersonCancerCenter, LeukemiaDepartment,1515Holcombe Address forcorrespondence: GloriaMattiuzzi,TheUniversity ofTexas mortality ratesassociatedwiththeseinfections. are athighriskofIFIiscriticaltoreduce themorbidityand understanding theriskfactorsandidentifyingpatientswho approach topatientsatlowriskofdevelopingIFI.Hence, the highestriskofIFI,andlimitpre-emptive–empirical advocated bysomehealthcare professionals. alternative strategyofempiricorpre-emptive therapyis toxicity, andemergence ofresistant species,and,therefore the use ofantifungalprophylaxis. Theconsequencesincludecost, not forthenegativeconsequencesassociatedwithroutine prophylaxis wouldbethemostappealingstrategyifitwere mortality anddiagnosticdifficulties associatedwithIFI, therapy (empiricorpre-emptive strategy).Giventhehigh (using antifungalagentsinaprophylactic mode)orearly mortality ratesinpatientswithIFI,whichfocusonprevention have beenemployedinanattempttoreduce morbidityand that are frequently associatedwithtoxicity. Severalstrategies and theneedforlong-termtreatment withexpensiveagents nature oftheseinfections,thelackreliable diagnostictests, hematological cancersisdifficult duetothelife-threatening infections (IFIs).ThemanagementofIFIinpatientswith increases theriskforinfections,includinginvasivefungal of therapysignificantlyaffects theimmunesystemand patients withhematologicalcancer. However, intensification during thepastfewdecadeshasimproved outcomesin The remarkable progress inanti-neoplastictherapiesachieved spectrum offungalinfectionsateachtreatmentcenter. The choiceoftheoptimalprophylacticstrategyshouldbemadeusingarisk-basedapproachandappropriatefor most likelytobenefitfromaprophylacticapproach.Severaloptionsareavailableinthesettingofantifungalprophylaxis. effects, includinghighcost,toxicity, andemergence ofresistantspecies.Thus,itisessentialtoidentifywhichpatientsar most appealingstrategies.However, theroutineandindiscriminateuseofantifungalprophylaxismayleadtoundesirable mortality rateanddiagnosticdifficulties associatedwithIFI,particularlymoldinfections,prophylaxis emergesasoneofthe Invasive fungalinfections(IFIs)causemorbidityandmortalityinpatientswithhematologicalmalignancies.Duetothehigh Department ofLeukemia,TheUniversityTexas MDAndersonCancerCenter, Houston,TX,USA Gloria NMattiuzziandHagopKantarjian with HematologicalCancers Antifungal Prophylaxis inPatients 10 Our strategyistoprovide prophylaxis forpatientswith T HE J UNLOF OURNAL I NVASIVE J InvasiveFungalInfect F UNGAL I Patients atrisk the needforrepeated application ofintensivecytotoxic patients withrelapsed orresistant disease.Thisisdueto [Mattiuzzi, unpublisheddata]. unknown origin).Noneof theinfectionsinvolvedfungi patients, (fourbacteremia, onesinusitis,and sixfeverof responsible forhospitalizationinonly11(22%)ofthe consolidation chemotherapy, revealed thatinfectionwas 49 patientswithAMLinremission whowere receiving during a6-monthperiod(June–November, 2001)among Indeed, anevaluationofthecausesforhospitalization substantially lower(<1%)duringthisphaseoftherapy. given duringremission induction;andtherisk ofIFIis even thoughanti-leukemiatreatment isasintensivethat from neutropenia ismuchfaster(approximately 2weeks), with moldinfections.Duringconsolidationtherapy, recovery mortality rateisunacceptablyhigh,especiallyforthose therapy, neutropenia (approximately 3weeks).Duringchemo- chemotherapeutic regimen, andtheresulting prolonged numbers ofgranulocytesatdiagnosis,theintensity therapy are athighriskofdevelopingIFIbecausethelow leukemia (AML)undergoing remission inductionchemo- the sameriskofIFI.Patientswithacutemyelogenous (Table 1)[1]. organ damage,and environmental exposure topathogens to theunderlyingdiseaseandcytotoxicchemotherapy), result from theinteractionofimmunosuppression (secondary malignancies appearathighestriskforIFI.RiskfactorsIFI Among patientswithcancer, thosewithhematological NFECTIONS Among AMLpatients,those athighestriskforIFIare Not allhematologicalmalignanciesare associatedwith ≤ V 25% ofAMLpatientsdevelopIFI,andthe OL 2007; 1 N O 1 1 2007 (1):10–6. e ANTIFUNGAL PROPHYLAXIS IN PATIENTS WITH HEMATOLOGICAL CANCERS

Table 1. Risk factors for invasive fungal infection in patients with hematological cancers. Risk factor Infection Population Microbial exposure Colonization and exposure Mucosal AML, autoBMT Cancer (exposure to antibiotics) Nasal Aspergillosis Hematological malignancies Cutaneous Hematological malignancies History of fungal infection Aspergillosis AML Fusariosis AML, ALL, lymphomas , Non-Hodgkin’s lymphoma Net state of immunosuppression* Broad immunosuppression Age (older) and mold infections Allo, autoBMT/PBSCT Myeloablative chemotherapy Yeast and mold infections Allo, autoBMT/PBSCT Low CD34+ stem cell dose Yeast and mold infections Allo, autoBMT/PBSCT Stem cell manipulation (CD34+ selection) Various infections Several patient populations Histocompatibility Invasive aspergillosis AlloBMT Extensive prior chemotherapy Several patient populations Interleukin-2 therapy Invasive aspergillosis Several patient populations Profound and persistent neutropenia** Aspergillosis, invasive candidiasis, AML, > solid tumors fusariosis Lymphopenia and CD4 cytopenia All causes Cryptococcosis AlloBMT Aspergillosis Therapy with nucleoside analogues Adrenal corticosteroids 1 to 2 mg/kg/day Aspergillosis, invasive candidiasis, All patients ≥3 to 5 weeks PCP, other Nucleoside analogues Yeast and mold infections CLL, lymphoma Campath-1H Yeast and mold infections CLL Refractory malignancy Yeast and mold infections Acute leukemias Organ dysfunction Gut Invasive candidiasis>other Mucositis after chemotherapy, radiotherapy PCP Malnutrition Renal Invasive candidiasis, aspergillosis RF PCP CLL Pulmonary All fungal infections All patients Pancreas (diabetes mellitus) Candidiasis, zygomycosis All patients Invasive candidiasis GVHD Cryptococcosis, candidiasis Sezary Syndrome Aspergillosis and infection with Trauma (CVC site) spp

*Immunosuppression may be limited to one arm of the immune system, or found in more than one arm (neutropenia, lymphopenia, asplenia, and others) in patients receiving myeloablative therapy. **Profound and persistent: <100 cells/µL ≥10 days. ALL: acute lymphocytic leukemia; allo: allogeneic; AML: acute myeloid leukemia; aspergillosis: invasive Aspergillus infection; auto: autologous; BMT: bone marrow; transplantation; candidiasis: invasive candidiasis; CLL: chronic lymphocytic leukemia; CVC: central venous catheter; GVHD: graft versus host disease; PBSCT: peripheral blood stem cell transplantation; PCP: Pneumocystis carinii pneumonia; RF: renal failure. Adapted with permission from [1]. therapies, which can result in prolonged neutropenia and Patients with acute lymphocytic leukemia (ALL) are other immunosuppression in patients who have been susceptible to IFI due to neutropenia and long-term exposed to fungi by colonization or by prior fungal infection exposure to high-dose corticosteroids. The incidence of IFI in during preceding therapies. 13% of ALL patients is similar to the incidence seen among

THE JOURNAL OF INVASIVE FUNGAL INFECTIONS VOL 1 NO 1 2007 11 GLORIA N MATTIUZZI AND HAGOP KANTARJIAN

patients with AML. IFIs in patients with AML and ALL impairment in cellular immunity, granulocytopenia, and predominantly involve Candida and Aspergillus spp. reduction of granulocyte function, all of which increase the However, the fungal-related mortality rate for ALL patients risk of IFI. Indeed, recent reports have described an increase is much lower compared with that in AML patients [2]. in the incidence of IFI, particularly invasive aspergillosis, in Possible explanations for this difference in mortality rate are: MM patients patients undergoing intensive chemotherapy with high-dose corticosteroids [9]. • The high remission rates achieved in ALL (approximately Risk factors for IFI among patients undergoing 90%) compared with AML (67%). hematopoietic stem-cell transplantation (HSCT) have been • The faster recovery from neutropenia in ALL compared well described, and the incidence of IFI varies according to with AML (18 days and 21 days, respectively). the type of transplant. The lowest incidence (0–5%) and best • The younger age of ALL patients (median 39.5 years) outcomes have been reported for recipients of autologous compared with AML patients (median 57 years) [3,4]. HSCT, regardless of the type of underlying disease [10–12]. However, increasing numbers of Aspergillus infections Although patients with relapsed ALL are thought to have among patients undergoing autologous HSCT have been an increased risk of IFI due to low response rates to salvage reported [13]. therapies (approximately 30%) and prolonged exposure IFI is more common among patients undergoing to high-dose corticosteroids [5], no findings have been allogeneic HSCT, with an incidence of 10–25%. The risk of published on the frequency of IFI in such patients. IFI varies during the transplantation period. During the Patients with chronic lymphocytic leukemia (CLL) are pre-engraftment period (≤30 days following transplant), also susceptible to infection due to therapy-related immuno- mucosal injury, neutropenia, and the development of acute suppression. Although bacterial infections predominate graft-versus-host disease (GVHD) are the major risk factors among such patients, IFI (especially from Candida spp or for IFI. The presence of acute and chronic GVHD and Aspergillus spp) may occur during prolonged neutropenia impaired cellular immunity influences the patient vulnerability secondary to treatment and concurrent use of corticosteroids to IFI during the post-engraftment period (30–100 days [6]. An incidence of IFI in patients with CLL of 7–12% has following transplant). During the late phase (>100 days after been reported among patients being treated with purine engraftment), impairments in cellular and humoral immunity analogues such as cladribine [7] or with monoclonal and chronic GVHD are the main factors influencing the risk antibodies such as alemtuzumab [8]. However, patients with of IFI. heavily treated CLL, or CLL that is resistant to fludarabine, Candida spp and Aspergillus spp remain the most have a greater risk of IFI [6]. common causes of IFI among patients undergoing HSCT, Lymphoid malignancies are usually associated with and C albicans and A fumigatus are the most common deficiencies in cell-mediated immunity, which may increase species implicated in IFI within this group of patients. the risk of infection from a variety of organisms, including However, it is important to recognize that infections with fungi. However, the spectrum of fungal infections in patients non-albicans Candida species (C glabrata and C krusei) and with lymphoid malignancies differs from that described for non-fumigatus Aspergillus species are becoming more other hematological malignancies, with Cryptococcus prevalent [13–15]. This shift in causative agent is of clinical neoformans, , and significance because these species of Candida and imminitis appearing to be the most common . Aspergillus may be more virulent and more difficult to treat. However, the type of therapy applied to such patients modifies their risk for IFI if prolonged neutropenia or other Available options and suggested use immunosuppression ensues, and this includes an increased for antifungal prophylaxis rate of candidiasis and aspergillosis. There are a number of classes of antifungal agents that may Therapy for chronic myelogenous leukemia is associated be considered for prophylaxis in hematological oncology with a very low risk of IFI, unless the disease is no longer in patients. The characteristics of currently available agents the early phase and more intensive therapies are applied. have been summarized in Table 2. Consequently, such patients will be at the same risk of IFI as are patients with newly diagnosed AML. Azoles Patients with multiple myeloma (MM) have classically has been widely used in patients with leukemia been considered to be at risk of infection with encapsulated and in recipients of HSCT. The benefits of using fluconazole bacteria due to hypogammaglobulinemia. However, during as a prophylactic agent include reduction in fungal colonization advanced stages of the disease, patients with MM also show and hematogenous candidiasis and, more importantly,

12 THE JOURNAL OF INVASIVE FUNGAL INFECTIONS VOL 1 NO 1 2007 ANTIFUNGAL PROPHYLAXIS IN PATIENTS WITH HEMATOLOGICAL CANCERS

Table 2. Characteristics of antifungal agents available for prophylaxis. Drug Spectrum Formulation Cost Fluconazole Yeasts PO, IV PO: $ IV: $$ Yeasts, molds PO, IV PO: $ IV: $$ Voriconazole Yeasts, molds PO, IV PO: $$ IV: $$$ Posaconazole Yeasts, molds, zygomycosis? PO $$$$ AmB Yeasts, molds, zygomycosis IV $ Liposomal AmB Yeasts, molds, zygomycosis IV $$$ AmB lipid complex Yeasts, molds, zygomycosis IV $$ AmB colloidal dispersion Yeasts, molds, zygomycosis IV $$ Yeastsa, moldsb IV $$$$ Yeastsa, moldsb IV $$$ Yeastsa, moldsb IV $$$

aexcluding spp. bexcluding spp, zygomycosis, others. $; inexpensive; $$: moderately expensive; $$$: expensive; $$$$: very expensive; AmB: ; IV: intravenous: PO: oral.

improved survival rates [16–18]. The excellent bioavailability duration of exposure to itraconazole (median 21 days) [22]. of fluconazole, superior safety profile, low cost, and its In summary, intravenous itraconazole can be considered for availability in oral and intravenous formulations make prophylaxis, especially for patients who cannot tolerate or fluconazole a good option for prophylaxis. However, with absorb oral medications and who need broad-spectrum the increasing rates of mold infections in high-risk patients antifungal coverage (yeasts and molds). Alternatively, the and the emergence of fluconazole-resistant Candida oral suspension formulation may be used in the outpatient infections, the use of fluconazole is becoming limited to setting following hospital discharge, with close monitoring smaller subgroups of leukemia patients at low risk of IFI, for the emergence of side effects. such as patients with AML in remission, those undergoing Some properties of voriconazole make it an attractive autologous HSCT, and those with CLL. option for antifungal prophylaxis. The agent is active against Itraconazole has potent antifungal activity against yeasts Aspergillus and Candida spp, and is available in both IV and and molds. Like fluconazole, it is available in oral and oral formulations with a >90% oral bioavailability. Although intravenous formulations, but reports of numerous side voriconazole has not yet been approved by the US Food and effects and drug interactions have limited its use. When Drugs Administration for prophylaxis, several institutions taken orally, the solution form is recommended over the have successfully used it for this purpose, reserving capsule form due to its superior bioavailability. The prophylactic voriconazole use for patients at particularly high superiority of the itraconazole suspension was demonstrated risk of IFI, such as those with acute leukemia and allogeneic in a meta-analysis, in which the incidence of Aspergillus HSCT [23,24]. Although voriconazole is generally well infection was only reduced in trials involving the use of oral tolerated, its use has been associated with transient suspension [19]. Furthermore, itraconazole oral solution elevations of liver transaminases and with reversible visual produces significantly fewer mold infections compared with disturbances. Furthermore, the possibilities of cross-resistance fluconazole oral solution [20,21]. Despite such encouraging of some Candida spp to fluconazole and voriconazole and evidence of efficacy and the low cost of itraconazole oral the emergence of zygomycosis have raised concerns regarding solution, this therapeutic agent suffers some limitations as a the prophylactic use of voriconazole. In an evaluation of prophylactic agent, including hepatic and gastrointestinal breakthrough Candida infections among patients receiving toxicity (nausea, vomiting, and diarrhea) [20,21]. different antifungal prophylactic regimens, an apparent Furthermore, concerns have been expressed regarding reduction was noted in the rate of C krusei infection with possible cardiotoxicity associated with the use of intravenous voriconazole prophylaxis (0 of 105 patients) compared with itraconazole. However, in one study of intravenous itraconazole prophylactic fluconazole (16 of 519 patients; p=0.069). prophylaxis for patients with AML, no cardiotoxicity could Fewer infections due to C glabrata were also observed with be demonstrated and stable cardiac ejection fractions by voriconazole prophylaxis (0 of 105 patients) compared with serial echocardiograms were observed, despite the median fluconazole or itraconazole recipients (18 of 1647). These age of the cohort (median 60 years) and the lengthy findings represent the first solid evidence indicating that

THE JOURNAL OF INVASIVE FUNGAL INFECTIONS VOL 1 NO 1 2007 13 GLORIA N MATTIUZZI AND HAGOP KANTARJIAN

there is no clinically significant cross-resistance between well tolerated at the doses used in these studies. Limitations fluconazole and voriconazole, and support in vitro studies on its use for prophylaxis are its high cost and the need indicating that voriconazole is effective against C krusei [25]. for frequent intravenous administration, which is often Despite its apparent efficacy, there is concern regarding inconvenient for patients. the use of voriconazole and the emergence of zygomycosis, New drug delivery strategies have been developed in the which has been reported in patients treated with HSCT who past few years. Two studies have explored the safety and developed GVHD [26–28]. However, the emergence of pharmacokinetics of weekly high-dose L-AmB for prophylaxis. zygomycosis was first observed several years before the In one study, L-AmB was given at a dose of 7.5 mg/kg once introduction of voriconazole [29] and additional data are weekly to 15 adults undergoing HSCT [36]. L-AmB was well needed to establish whether or not the emergence of tolerated, with mild and transitory infusion-related reactions. zygomycosis in these HSCT patients was linked solely to Four patients required drug discontinuation because of the use of voriconazole. Overall, voriconazole has been increased creatinine levels. In another study, 14 children were effective at preventing breakthrough IFI and has been well given L-AmB at 10 mg/kg once per week, and the results tolerated when used in patients with newly diagnosed acute confirmed the safety of this strategy [37). Importantly, tissue leukemia [24]. concentrations of L-AmB given at single dose of 15 mg/kg Posaconazole was approved in 2006 for IFI prophylaxis every 2 weeks were similar to those when L-AmB was given in patients undergoing HSCT and in patients with hematological daily at 1 mg/kg to patients undergoing peripheral stem cell malignancies who were expected to have prolonged transplant [38]. Further studies are needed to accurately neutropenia from chemotherapy. In a randomized trial of evaluate the safety and efficacy of using high-dose antifungal prophylaxis in patients with AML that compared intermittent L-AmB for IFI prophylaxis. oral posaconazole with oral fluconazole or itraconazole [30], The safety of aerosolized AmB in lipid complexes for posaconazole more effectively prevented IFI (mostly Aspergillus prophylaxis has been demonstrated in patients aspergillosis) and led to significantly improved survival. undergoing lung transplantation [39], and (in combination Unfortunately, the overwhelming majority of patients in the with intravenous fluconazole) in recipients of HSCT [40]. control group received fluconazole, an agent known to be Indeed, adverse events such as nausea, vomiting, and taste devoid of activity against aspergillosis. Furthermore, details disturbances occurred in 2–7.5% of patients given the on the patient population studied are not yet available. Since aerosolized form compared with 69% of patients given posaconazole is not available in an intravenous formulation aerosolized conventional amphotericin B [41]. In a lung and patients with severe mucositis have low absorption transplant study, six of the 51 patients (12%) given aerosolized rates, it is particularly important to determine the tolerance AmB developed IFIs, but none were lung parenchymal for oral therapy in the subjects of this study [31]. However, infections [35]. In the HSCT study, none of the patients given posaconazole was generally well tolerated; drug-related aerosolized AmB in combination with fluconazole developed adverse events were typical of those associated with the IFIs in the lungs, and only one patient developed cutaneous azoles (increased values in liver function tests, nausea, and fusariosis, suggesting that the aerosolized form was not vomiting), and the incidence of side effects was comparable systematically absorbed. Thus, from a safety point of view, in the two study arms. Posaconazole must be given three aerosolized AmB is relatively well tolerated. Additional times per day, and in combination with high-fat, high-calorie studies are needed to confirm its prophylactic activity in this meals for optimal absorption. However, this is frequently patient population. not possible among patients with hematological cancers undergoing intensive cytotoxic chemotherapy, and who may Echinocandins therefore be suffering from severe mucositis, nausea, Three echinocandins are currently available in the US, vomiting, and severe diarrhea. but information on their use for prophylaxis is only available for two of the agents, caspofungin and micafungin. The Polyenes safety of these echinocandins and their lack of interaction Of the three amphotericin B lipid formulations currently with other drugs are attractive attributes, and have been available from commercial sources, liposomal amphotericin B confirmed in two recent studies [22,42]. When micafungin (L-AmB) has been the most frequently used for prophylaxis. was compared with fluconazole in patients undergoing Some studies have suggested that low-dose L-AmB HSCT, fewer patients in the micafungin group required drug (1–3 mg/kg) given three times per week was as effective discontinuation due to adverse events, and the number of in reducing the rates of IFI or fungal-related mortality as drug-related side effects were comparable between the two amphotericin B lipid complex [32–35]. In general, L-AmB is groups [42]. Hyperbilirubinemia, allergy-related reactions,

14 THE JOURNAL OF INVASIVE FUNGAL INFECTIONS VOL 1 NO 1 2007 ANTIFUNGAL PROPHYLAXIS IN PATIENTS WITH HEMATOLOGICAL CANCERS

histamine-related reactions, nausea, and diarrhea were the References most common side effects from micafungin therapy. In a 1. Mahfouz T, Anaissie E. Prevention of fungal infections in the immunocompromised host. Curr Opin Invest Drugs 4 comparison of caspofungin and intravenous itraconazole for 2003; :974–90. 2. Cabanillas ME, Mattiuzzi G, Thomas D et al. Invasive fungal infections in patients receiving prophylaxis in patients with acute leukemia, fewer caspofungin- hyper-CVAD. Abstract 6727. J Clin Oncol 2004;22(14S):6727. 3. Kantarjian HM, O’Brien S, Smith TL et al. Results of treatment with hyper-CVAD, a dose- treated patients than itraconazole-treated patients were intensive regimen, in adult acute lymphocytic leukemia. J Clin Oncol 2000;18:547–61. withdrawn from the study due to side effects [22]. 4. Estey E, Shen Y, Thall PF. Effect of time to complete remission on subsequent survival Despite the activity of echinocandins against a broad range and disease-free survival time in AML, RAEB-t, and RAEB. Blood 2000;95:72–7. 5. Thomas DA, Kantarjian H, Smith TL et al. Primary refractory and relapsed adult acute of Candida spp, breakthrough infections from C parapsilosis lymphoblastic leukemia: characteristics, treatment results, and prognosis with salvage therapy. Cancer 1999;86:1216–30. and C guilliermondii have been reported, confirming 6. Wadhwa PD, Morrison VA. Infectious complications of chronic lymphocytic leukemia. reports of high minimal inhibitory concentrations for these Semin Oncol 2006;33:240–9. 7. Robak T, Blonski JZ, Kasznicki M et al. Cladribine with or without prednisone in the organisms [43]. Another caveat for echinocandins is their treatment of previously treated and untreated B-cell chronic lymphocytic leukaemia – limited activity against Trichosporon spp and Fusarium spp, updated results of the multicentre study of 378 patients. Br J Haematol 2000;108:357–68. 8. Keating M, Coutre S, Rai K et al. Management guidelines for use of alemtuzumab and against the agents of zygomycosis. Because echinocandins in B-cell chronic lymphocytic leukemia. Clin Lymphoma 2004;4:220–7. have an excellent safety profile and broad-spectrum activity 9. Lortholary O, Ascioglu S, Moreau P et al. Invasive aspergillosis as an opportunistic infection in nonallografted patients with multiple myeloma: a European Organization against yeasts and molds, presumably these drugs will be for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group most frequently used in patients with a particularly high risk and the Intergroupe Francais du Myelome. Clin Infect Dis 2000;30:41–6. 10. Auner HW, Sill H, Mulabecirovic A et al. Infectious complications after autologous of IFI. Thus, special attention should be paid to the hematopoietic stem cell transplantation: comparison of patients with acute myeloid possibility of breakthrough or emerging IFIs in such patients, leukemia, malignant lymphoma, and multiple myeloma. Ann Hematol 2002;81:374–7. 11. Jantunen E, Salonen J, Juvonen E et al. Invasive fungal infections in autologous stem cell particularly those caused by Trichosporon spp or Fusarium transplant recipients: a nation-wide study of 1188 transplanted patients. Eur J Haematol 2004;73:174–8. spp, and the agents of zygomycosis. Finally, the longer half- 12. Offidani M, Corvatta L, Olivieri A et al. Infectious complications after autologous lives of anidulafungin and micafungin may allow for less peripheral blood progenitor cell transplantation followed by G-CSF. Bone Marrow Transplant 1999;24:1079–87. frequent dosing schedules. 13. Marr KA, Carter RA, Crippa F et al. Epidemiology and outcome of mould infections in hematopoietic stem cell transplant recipients. Clin Infect Dis 2002;34:909–17. 14. Marr KA, Seidel K, White TC et al. Candidemia in allogeneic blood and marrow transplant Conclusion recipients: evolution of risk factors after the adoption of prophylactic fluconazole. New and increasingly intensive treatments for hematological J Infect Dis 2000;181:309–16. 15. Wingard JR, Merz WG, Rinaldi MG et al. Increase in infection among malignancies will undoubtedly continue to be developed patients with bone marrow transplantation and neutropenia treated prophylactically and, as a consequence, the risk of IFI will continue to with fluconazole. N Engl J Med 1991;325:1274–7. 16. Goodman JL, Winston DJ, Greenfield RA et al. A controlled trial of fluconazole to prevent increase. Therefore, until difficulties in the diagnosis of IFI fungal infections in patients undergoing bone marrow transplantation. N Engl J Med are resolved, antifungal prophylaxis will still have a key role 1992;326:845–51. 17. Slavin MA, Osborne B, Adams R et al. Efficacy and safety of fluconazole prophylaxis for in reducing fungal-related morbidity and mortality rates fungal infections after marrow transplantation—a prospective, randomized, double-blind study. J Infect Dis 1995;171:1545–52. among high-risk patients. The choice of the optimal 18. Marr KA, Seidel K, Slavin MA et al. Prolonged fluconazole prophylaxis is associated prophylactic strategy (which drug, at what dose, and for with persistent protection against candidiasis-related death in allogeneic marrow transplant recipients: long-term follow-up of a randomized, placebo-controlled trial. how long) is likely to be related to the specific type of risk Blood 2000;96:2055–61. group and to the spectrum of fungal infections at each 19. Glasmacher A, Prentice A, Gorschluter M et al. Itraconazole prevents invasive fungal infections in neutropenic patients treated for hematologic malignancies: evidence from treatment center. Risk factors for IFI, which differ among a meta-analysis of 3,597 patients. J Clin Oncol 2003;21:4615–26. various patients, play an important role in the decision 20. Winston DJ, Maziarz RT, Chandrasekar PH et al. Intravenous and oral itraconazole versus intravenous and oral fluconazole for long-term antifungal prophylaxis in allogeneic to use prophylaxis and in the selection of the optimal hematopoietic stem-cell transplant recipients. A multicenter, randomized trial. Ann Intern Med 2003;138:705–13. strategy. The risk of IFI is the result of the interaction 21. Marr KA, Crippa F, Leisenring W et al. Itraconazole versus fluconazole for prevention between environmental exposure to fungi, intensity of of fungal infections in patients receiving allogeneic stem cell transplants. Blood 2004;103:1527–33. immunosuppression, and the presence of organ dysfunction. 22. Mattiuzzi GN, Alvarado G, Giles FJ et al. Open-label, randomized comparison of In short, a risk-based approach to prophylaxis is needed that itraconazole versus caspofungin for prophylaxis in patients with hematologic malignancies. Antimicrob Agents Chemother 2006;50:143–7. will address the requirements of each group of patients. 23. Siwek GT, Pfaller MA, Polgreen PM et al. Incidence of invasive aspergillosis among allogeneic hematopoietic stem cell transplant patients receiving voriconazole prophylaxis. The objective of this strategy is to choose an antifungal Diagn Microbiol Infect Dis 2006;55:209–12. medication from the existing armamentarium and use it in 24. Mattiuzzi GN, Estey EH, Hernandez M et al. Voriconazole and liposomal amphotericin B (Ambisome) effectively prevent mold infections in patients (pts) with acute myelogenous the most effective way possible, while avoiding toxicity, leukemia (AML) following remission induction chemotherapy (ric) [ASH Annual Meeting overuse, and the development of drug resistance. Abstract]. Blood 2005;106:2773. 25. Mattiuzzi GN, Cabanillas M, Hernandez M et al. Breakthrough Candida infections in patients with leukemia: the impact of antifungal prophylaxis on Candida species [Abstract P-032]. Presented at The 16th Focus on Fungal Infections Meeting, Las Vegas, NV, USA, Disclosure 2006. (winner, Thomas J Walsh Mycology Award) Dr Mattiuzzi has been a speaker for Pfizer and Merck, and has received 26. Marty FM, Cosimi LA, Baden LR. Breakthrough zygomycosis after voriconazole treatment in recipients of hematopoietic stem-cell transplants. N Engl J Med 2004;350:950–2. research grants from MGI, and Astellas. Dr Kantarjian has received 27. Imhof A, Balajee SA, Fredricks DN et al. Breakthrough fungal infections in stem cell research grants from Novartis, MGI and BMS. transplant recipients receiving voriconazole. Clin Infect Dis 2004;39:743–6.

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28. Siwek GT, Dodgson KJ, de Magalhaes-Silverman M et al. Invasive zygomycosis in 36. El-Cheikh J, Faucher C, Furst S et al. Safety of a weekly administration of 7.5 mg/kg hematopoietic stem cell transplant recipients receiving voriconazole prophylaxis. of liposomal amphotericin B (LAB) for antifungal prophylaxis in patients receiving high Clin Infect Dis 2004;39:584–7. dose corticosteroids (CS) for acute GVHD after reduced intensity conditioning (RIC) allogeneic stem cell transplantation (allo-SCT) [ASH Annual Meeting Abstract]. 29. Kontoyiannis DP, Wessel VC, Bodey GP et al. Zygomycosis in the 1990s in a tertiary-care Blood 2005;106:5348. cancer center. Clin Infect Dis 2000;30:851–6. 37. Mehta P, Vinks A, Filipovich A et al. High-dose weekly AmBisome antifungal prophylaxis in 30. Cornely O, Maertens J, Winston D et al. Posaconazole vs standard azole (FLU/ITRA) pediatric patients undergoing hematopoietic stem cell transplantation: a pharmacokinetic therapy for prophylaxis of invasive fungal Infections (IFIs) among high-risk neutropenic study. Biol Blood Marrow Transplant 2006;12:235–40. patients: results of a randomized, multicenter trial. Blood 2005;106:1844. 38. Gubbins PO, McConnell SA, Amsden R et al. Comparison of Liposomal Amphotericin B 31. Gubbins PO, Krishna G, Sansone-Parsons A et al. Pharmacokinetics and safety of oral Plasma and Tissue Concentrations following a single Large (15 mg/kg) Dose or Daily posaconazole in neutropenic stem cell transplant recipients. Antimicrob Agents Chemother 1 mg/kg Dosing [Abstract A-33].Presented at The 44th Interscience Conference on 2006;50:1993–9. Antimicrobial Agents and Chemotherapy (ICAAC) Washington, DC, USA, 2004. 32. Kelsey SM, Goldman JM, McCann S et al. Liposomal amphotericin (AmBisome) in the 39. Palmer SM, Drew RH, Whitehouse JD et al. Safety of aerosolized amphotericin B lipid prophylaxis of fungal infections in neutropenic patients: a randomised, double-blind, complex in lung transplant recipients. Transplantation 2001;72:545–8. placebo-controlled study. Bone Marrow Transplant 1999;23:163–8. 40. Alexander BD, Wingard JR. Study of renal safety in amphotericin B lipid complex-treated 33. Tollemar J, Ringden O, Andersson S et al. Randomized double-blind study of liposomal patients. Clin Infect Dis 2005;40(Suppl 6):S414–21. amphotericin B (Ambisome) prophylaxis of invasive fungal infections in bone marrow 41. Gryn J, Goldberg J, Johnson E et al. The toxicity of daily inhaled amphotericin B. transplant recipients. Bone Marrow Transplant 1993;12:577–82. Am J Clin Oncol 1993;16:43–46. 34. Uhlenbrock S, Zimmermann M, Fegeler W et al. Liposomal amphotericin B for prophylaxis 42. van Burik JA, Ratanatharathorn V, Stepan DE et al. National Institute of Allergy and of invasive fungal infections in high-risk paediatric patients with chemotherapy-related Infectious Diseases Mycoses Study Group. Micafungin versus fluconazole for prophylaxis neutropenia: interim analysis of a prospective study. Mycoses 2001;44:455–63. against invasive fungal infections during neutropenia in patients undergoing hematopoietic 35. Mattiuzzi GN, Estey E, Raad I et al. Liposomal amphotericin B versus the combination of stem cell transplantation. Clin Infect Dis 2004;39:1407–16. fluconazole and itraconazole as prophylaxis for invasive fungal infections during induction 43. Ostrosky-Zeichner L, Rex JH, Pappas PG et al. Antifungal susceptibility survey of chemotherapy for patients with acute myelogenous leukemia and myelodysplastic 2,000 bloodstream Candida isolates in the United States. Antimicrob Agents Chemother syndrome. Cancer 2003;97:450–6. 2003;47:3149–54.

16 THE JOURNAL OF INVASIVE FUNGAL INFECTIONS VOL 1 NO 1 2007 CASE STUDY 17 1 2007 O 1 N OL V Clinical aspect at onset of infection showing Clinical aspect at onset Magnetic resonance imaging scan showing ethmoidal Magnetic resonance Figure 2. of soft tissue of the inner part of the right sinusitis and necrosis orbit (arrows). Figure 1. the right conjunctiva and eyelids. inflammatory signs of at the inner junction of the right area is a necrotic There (arrow). lower and upper eyelids NFECTIONS I l), μ UNGAL F grew L; no μ E cloacae Escherichia NVASIVE I and OURNAL OF (1):17–8. J 1 HE T 2007; Enterobacter cloacae .

E coli bacteremia. Four days before hospitalization, the patient hospitalization, Four days before bacteremia.

Because a filamentous fungal infection was suspected, Because a filamentous fungal infection At admission the patient had mild anemia (hemoglobin At admission the patient had mild anemia was still severely Six days after admission, the patient Address for correspondence: Raoul Herbrecht, Department of Hematology Raoul Herbrecht, for correspondence: Address France. 67098 Strasbourg, Hôpital de Hautepierre, and Oncology, Email: [email protected] Histopathology showed numerous broad, hyaline, non- broad, Histopathology showed numerous branching at right angles, which septate hyphae that were was suggestive of zygomycosis. Mycology from nasal swab and samples, confirming the nasal swab from suspicion of zygomycosis. A 62-year-old woman was hospitalized for febrile woman A 62-year-old to related neutropenia therapy was initiated. amphotericin B lipid complex (ABLC) rapidly with an Nevertheless, clinical condition worsened inflammatory signs of the of an increase of fever, increase conjunctiva and eyelids, and the appearance of a very small zone at the inner junction of the right lower and necrotic imaging scan upper eyelids (Fig. 1). A magnetic resonance and sinusitis, showed ethmoidal sinusitis, bilateral frontal of the inner wall of the right orbit, and it confirmed necrosis that the infection had extended to the brain (Figs. 2 and 3). J Invasive Fungal Infect J Invasive Fungal (platelet count 5000/ thrombocytopenia 10.4 g/dL), severe the right upper and she developed edema of neutropenic A cranial computed tomography scan eyelid and a new fever. sinusitis, ethmoidal and frontal showed bilateral maxillary, lobes, nearly complete right nasal hypodensity in both frontal in the right nasal obstruction, mild thickening of soft tissue but no evidence of bone destruction. and orbital area, Case study presented by Raoul Herbrecht, Caroline Berthillot, and Cécile Fohrer and Cécile Berthillot, Caroline by Raoul Herbrecht, presented Case study France Strasbourg, Hôpital de Hautepierre, coli high-dose a chemotherapy cycle combining had received nervous system and cytarabine for a central methotrexate lymphoma. of non-Hodgkin’s relapse piperacillin/ The patient was administered count). differential rapidly disappeared tazobactam and amikacin. Her fever found to be negative for were and blood cultures and Rhino-Orbito-Cerebral Zygomycosis Rhino-Orbito-Cerebral and severe neutropenia (white blood cell count <100/ neutropenia and severe RAOUL HERBRECHT, CAROLINE BERTHILLOT, AND CÉCILE FOHRER

Figure 3. Magnetic resonance imaging scan showing bilateral Figure 4. Clinical aspect after 2 weeks showing a decrease frontal sinusitis and extension of the infection to both frontal of inflammatory signs but an increase in the size of the lesion, lobes of the brain (arrows). with fistula to the nasal cavity. There is persistence of necrotic tissues.

Outcome Surgery was not considered to be possible because of the substantial brain involvement. Infection progressed locally (Fig. 4) and then spread to the lung (Fig. 5), despite the patient’s recovery from neutropenia. Therapy was then Figure 5. Chest computed tomography scan showing a switched to posaconazole, after 3 weeks of ABLC. The nodular lesion in the right lung consistent with a pulmonary patient’s condition continued to worsen and she died localization of the zygomycosis. 49 days after the first clinical signs. Causes of death were the infection and the relapse of the lymphoma. R pusillus still grew from post mortem nasal biopsy samples.

Discussion Zygomycosis is an invasive disease caused by fungi from the order and the order. In a large literature review, R pusillus was found to be involved in 4% of the reported cases, the most frequently isolated organisms being spp [1]. Zygomycosis mainly affects patients who are intravenous drug abusers, who have undergone organ or hematopoietic stem cell transplantation, or who have diabetes, renal failure, HIV infection, or a hematological malignancy or solid tumor [1,2]. The most frequent primary sites of infection are the paranasal sinuses, the lungs, the skin, and the digestive tract. Zygomycotic agents are usually susceptible to amphotericin B, and many of them are also susceptible to Disclosures posaconazole [3]. The agents are resistant to the other newer Dr Herbrecht has been a member of an advisory board or speaker’s bureau azoles and to the echinocandins. Surgical removal of the for Astellas, Gilead, Merck, Pfizer, Schering-Plough, and Zeneus. Drs infected and necrotic tissue is an important part of the Berthillot and Fohrer have no relevant financial relationships to disclose. therapeutic strategy. However, despite in vitro sensitivity to amphotericin B, outcome is generally poor, with an overall References mortality rate of >50% [1]. Prognosis of infection is closely 1. Roden MM, Zaoutis TE, Buchanan WL et al. Epidemiology and outcome of zygomycosis: related to the severity and evolution of underlying a review of 929 reported cases. Clin Infect Dis 2005;41:634–53. 2. Ribes JA, Vanover-Sams CL, Baker DJ. Zygomycetes in human disease. Clin Microbiol Rev immunosuppressed condition, and therefore failure rates are 2000;13:236–301. higher in transplant recipients and leukemia patients than in 3. Sun QN, Fothergill AW, McCarthy DI et al. In vitro activities of posaconazole, itraconazole, voriconazole, amphotericin B, and fluconazole against 37 clinical isolates of zygomycetes. patients with diabetes [1]. Antimicrob Agents Chemother 2002;46:1581–2.

18 THE JOURNAL OF INVASIVE FUNGAL INFECTIONS VOL 1 NO 1 2007 CLINICAL REVIEWS Commentary and Analysis on Recent Key Papers

Clinical reviews were prepared by...

CANDIDIASIS Although C albicans remains the most common causative agent for VVC, there has been a shift in recent years towards non-albicans Candida spp, particularly Genital Candida species detected in samples C glabrata. Two factors are thought to have contributed from women in Melbourne, Australia, before to this change: and after treatment with antibiotics Pirotta MV, Garland SM • The frequent use of over-the-counter topical antifungals. J Clin Microbiol 2006;44:3213–7. • The increased use of oral fluconazole in the community [1]. The authors of this study recruited women prescribed antibiotics who had no vaginal symptoms of vulvovaginal C albicans shows greater susceptibility to these products candidiasis (VVC) to investigate the incidence of genital compared with non-albicans Candida spp. colonization by Candida spp before and after treatment. Non-albicans VVC appears to be prominent in specific At baseline, 21% of subjects had Candida spp vaginal patient populations, especially in patients with recurrent colonization, and this value rose to 37% following antibiotic disease. In a recent epidemiological study in pregnant therapy. C albicans was the predominant agent isolated. women, 36.7% of all Candida isolates were non-albicans Baseline colonization and self-reported proneness to VVC Candida spp, with C glabrata accounting for 25.1% of all were independent predictors of post-antibiotic VVC. Candida isolates and 68.5% of non-albicans isolates [2]. The prevalence of C glabrata increased slightly with Vulvovaginal candidiasis (VVC) is a very common condition, progression of pregnancy from the first to the second and with approximately three out of every four women third trimesters. developing at least one episode of VVC during their lifetime. Postmenopausal women in long-term care facilities However, the epidemiology of this disease is changing. represent another population at high risk of colonization In this paper, the authors described the characteristics of with non-albicans Candida spp. Dan et al. tested VVC within a prospective cohort of 233 women receiving 106 bedridden residents of a long-term care facility. Of the antibiotic therapy in Melbourne (VIC, Australia). study patients, 32% had vaginal colonization with Candida Participants self-collected a low vaginal swab before and spp, and C glabrata was the predominant species isolated 8 days after completion of antibiotic treatment; data on from these women (51.2% of isolates) [3]. potential risk factors for VVC were collected at the same Knowledge of the risk factors for non-albicans VVC time. The rate of Candida spp colonization was 21% is necessary for prompt and efficient treatment for (95% confidence interval [CI] 17–27%) at baseline, rising to patients who do not respond to traditional antifungal 37% (95% CI 31–44%) after treatment. Overall, Candida therapy. Routine speciation may be warranted in specific albicans was the most common species, being detected patient populations. in 73% of subjects, with identified in 1. Martens MG, Hoffman P, El-Zaatari M. Fungal species changes in the female genital tract. J Low Genit Tract Dis 2004;8:21–4. approximately 20%. Self-reported proneness to VVC 2. Wenjin Q, Yifu S. Epidemiological study on vaginal Candida glabrata isolated from after antibiotic treatment and baseline colonization with pregnant women. Scand J Infect Dis 2006;38:49–54. 3. Dan M, Segal R, Marder V et al. Candida colonization of the vagina in elderly residents Candida spp were predictors of symptomatic VVC after of a long-term-care hospital. Eur J Clin Microbiol Infect Dis 2006;25:394–6. antibiotic treatment, and VVC symptoms had a sensitivity Address for reprints: MV Pirotta, Department of General Practice, of 57% and a specificity of 91% for microbiologically University of Melbourne, 200 Berkeley Street, Carlton, VIC 3053, proven candidiasis. Australia. Email: [email protected]

THE JOURNAL OF INVASIVE FUNGAL INFECTIONS VOL 1 NO 1 2007 19 CLINICAL REVIEWS

Molecular detection and identification Although the MagNA Pure method gave a lower DNA yield, of Candida and Aspergillus spp. from it was as time-efficient as the bead-beating method. clinical samples using real-time PCR Attempts to increase the DNA yield of the automated Klingspor L, Jalal S. technique resulted in more preparation steps, thereby increasing Clin Microbiol Infect 2006;12:745–53. the extraction time and obviating the need for automation. In another study, White et al. compared different PCR This study describes a real-time polymerase chain reaction techniques for Aspergillus and Candida spp [2]. The authors (PCR) method for the detection and speciation of Candida found that the detection limit of the Roche LightCycler was and Aspergillus spp in a variety of clinical samples. The test greatly reduced with whole-blood samples. achieved 100% specificity for both Candida and Aspergillus In conclusion, more studies are needed to determine the spp Positive PCR results for Candida and Aspergillus were optimal PCR technique for the detection of fungal pathogens. 1. Griffiths LJ, Anyim M, Doffman SR et al. Comparison of DNA extraction methods for corroborated by clinical or laboratory evidence of infection Aspergillus fumigatus using real-time PCR. J Med Microbiol 2006;55:1187–91. in 83% and 50% of cases, respectively. More studies are 2. White PL, Barton R, Guiver M et al. A consensus on fungal polymerase chain reaction diagnosis? A United Kingdom–Ireland evaluation of polymerase chain reaction methods needed to determine the optimal PCR technique for the for detection of systemic fungal infections. J Mol Diagn 2006;8:376–84. detection of fungal pathogens. Address for reprints: L Klingspor, Division of Clinical Bacteriology F82, Karolinska University Hospital Huddinge, SE-141 86 Stockholm, Traditional techniques for diagnosing systemic fungal Sweden. Email: [email protected] infections are subject to a variety of limitations; there is therefore great interest in developing and optimizing Evaluation of caspofungin and amphotericin molecular diagnostic methods. Several polymerase chain B deoxycholate against reaction (PCR) techniques have been developed that involve biofilms in an experimental intravascular various DNA extraction and amplification methods. catheter infection model The authors of the present article describe the Shuford JA, Rouse MS, Piper KE et al. performance of a real-time PCR assay for the detection of J Infect Dis 2006;194:710–3. Candida and Aspergillus spp. The automated MagNA Pure DNA isolation kit (Roche, Mannheim, Germany) was used In this rabbit model of Candida albicans intravascular for DNA extraction, and PCR amplification was performed catheter infection, animals (n=48) were randomly assigned using the LightCycler system (Roche, Mannheim, Germany) to a control, caspofungin, or amphotericin B (AmB) arm, and with oligonucleotide probes designed based on the sequences received treatment for 7 days. Significant decreases in fungal of the 18S rRNA genes of different fungal pathogens. PCR colony counts on the catheters were observed in the AmB identified Aspergillus and Candida to the genus level. For and caspofungin arms compared with the control arm. Candida-positive samples, typing to the species level was achieved using species-specific probes. The test achieved Candida spp are increasingly recognized as nosocomial 100% specificity for both Candida and Aspergillus spp and pathogens that cause a variety of infections, including had a sensitivity of 2 CFU/mL of blood. To assess the utility catheter-related bloodstream infections. One of the important of the assay in a clinical setting, the authors analyzed virulence factors of Candida is its ability to form biofilms, 1650 consecutive samples (1330 blood samples, 295 samples which make infections involving intravascular catheters more from other body fluids, and 25 biopsy samples) obtained difficult to eradicate. In the present study, the authors from patients with suspected invasive fungal infections. investigated the efficacy two antifungal agents in the Of these, 5.3% tested positive for Candida spp and 1.7% treatment of an experimental model of intravascular catheter were positive for Aspergillus spp. Verification of the results Candida albicans infection. Rabbits were randomly assigned using conventional methods was possible in 83% and 50% to a control arm or to receive systemic and intraluminal lock of cases, respectively. therapy with either caspofungin or amphotericin B (AmB) DNA extraction from fungi is technically difficult due to for 7 days. Catheters were cultured 24 h after the final the presence of a hardy cell wall that is resistant to lysis, treatment. C albicans was cultured from catheters from all and a number of manual and automated extraction methods rabbits in the control arm, from three in the AmB arm, and have been described. In a recent study, six extraction from no rabbits in the caspofungin arm. Colony counts were methods for Aspergillus fumigatus were compared [1]. The significantly higher in the control arm than in the AmB and bead-beating method followed by extraction with AL lysis caspofungin arms (both p<0.001). buffer (Qiagen, Hilden, Germany) was the most successful In vitro studies have demonstrated that echinocandins and least time-consuming extraction technique investigated. have potent activity against C albicans biofilms. Although the

20 THE JOURNAL OF INVASIVE FUNGAL INFECTIONS VOL 1 NO 1 2007 ASPERGILLOSIS

mechanism of action of echinocandins against fungal biofilms detect galactomannan, a polysaccharide cell wall product is still not completely understood, it is thought that released by Aspergillus spp. Several studies have examined echinocandins could lead to lysis and dissolution of the the sensitivity and specificity of this test in various clinical extracellular matrix by inhibiting polysaccharide production [1]. settings and patient populations. Adding to our knowledge Whether or not all echinocandins exhibit the same in this arena, the authors of the present article describe activity against fungal biofilms remains to be determined. three patients with invasive capitatum infections However, there is evidence that echinocandins have with positive Aspergillus galactomannan ELISAs. Although differential activity against the various Candida spp. For all three patients had acute leukemia, none showed evidence instance, in a recent in vitro study, micafungin was active of invasive aspergillosis. Further in vitro testing of 17 G against C kefyr and C glabrata biofilms, but not against capitatum strains confirmed the cross-reactivity with the C albicans, C dubliniensis, C tropicalis, or C parapsilosis galactomannan test. biofilms on polystyrene sections. Conversely, in a study on In a recent meta-analysis, the galactomannan assay had central venous catheter sections, micafungin was active against a pooled specificity of 93% for proven or probable invasive C glabrata, C parapsilosis, and C albicans biofilms, but not aspergillosis (estimates of specificity ranged from 60% in against C dubliniensis, C tropicalis, or C kefyr biofilms [2]. pediatric populations to 95% in patients with hematological In 2004, Shinabeck et al. developed a rabbit model of malignancies, using a cut-off value for positivity of 1.5) [1]. C albicans biofilm infection [3]. They showed that liposomal In addition to G capitatum, Giacchino et al. list other AmB lock therapy almost completely clears the biofilm. fungi that have been shown to cause false-positive However, more data are needed to determine the activity Aspergillus galactomannan tests, including infections with of liposomal AmB compared with AmB deoxycholate Penicillium marneffei [2] and Penicillium sp [3], and one and echinocandins. case of cryptococcosis [4]. It is notable that non-fungal Finally, although efforts are made to ensure the causes of cross-reactivity have been reported. A recent study applicability of the animal models to infection in humans, the of a variety of bacterial organisms found that most value of echinocandins and AmB in treating Candida biofilm Bifidobacterium spp and Eggerthella lenta gave false- infections needs to be demonstrated in human studies. positive galactomannan assays because of a lipoglycan 1. Jabra-Rizk MA, Falkler WA, Meiller TF. Fungal biofilms and drug resistance. Emerg Infect component in the cell membrane [5]. In another report, a Dis 2004;10:14–9. 2. Seidler M, Salvenmoser S, Muller FM. In vitro effects of micafungin against Candida patient with acute lymphoblastic leukemia and gastrointestinal biofilms on polystyrene and central venous catheter sections. Int J Antimicrob Agents graft-versus-host disease had a false-positive galactomannan 2006;28:568–73. 3. Schinabeck MK, Long LA, Hossain MA et al. Rabbit model of Candida albicans biofilm assay, which was ascribed to a nutrient formula containing infection: liposomal amphotericin B antifungal lock therapy. Antimicrob Agents Chemother 2004;48:1727–32. soybean protein [6]. Results obtained using the Aspergillus galactomannan Address for reprints: R Patel, Division of Infectious Diseases, Department assay need to be interpreted carefully. Given that lower of Medicine, Mayo Clinic College of Medicine, 200 First Street South West, Rochester, MN 55905, USA. Email: cut-off points for positivity are now recommended (≥0.5), false-positive results may become more frequent. A positive galactomannan assay can be relied upon to diagnose true [email protected] invasive aspergillosis only in the right clinical setting. Repeated positive results are more predictive of infection Aspergillus galactomannan enzyme-linked than a single assay. immunosorbent assay cross-reactivity caused 1. Pfeiffer CD, Fine JP, Safdar N. Diagnosis of invasive aspergillosis using a galactomannan assay: a meta-analysis. Clin Infect Dis 2006;42:1417–27. by invasive Geotrichum capitatum 2. Rimek D, Zimmermann T, Hartmann M et al. Disseminated Penicillium marneffei infection Giacchino M, Chiapello N, Bezzio S et al. in an HIV-positive female from Thailand in Germany. Mycoses 1999;42(Suppl 2):25–8. 3. Maertens J, Verhaegen J, Lagrou K et al. Screening for circulating galactomannan as a J Clin Microbiol 2006;44:3432–4. nonivasive diagnositic tool for invasive aspergillosis in prolonged neutropenic patients and stem cell transplantation recipients: a prospective validation. Blood 2001;97:1604–10. 4. Dalle F, Charles PE, Blanc K et al. galactomannan contains The authors of the present study demonstrate cross- an epitorpe(s) that is cross-reactive with Aspergillus galactomannan. J Clin Microbiol 2005;43:2929–31. reactivity of the Aspergillus galactomannan enzyme- 5. Mennink-Kersten MA, Ruegebrink D, Klont RR. Bifidobacterial lipoglycan as a new cause for false-positive Platelia Aspergillus enzyme-linked immunosorbent assay reactivity. linked immunosorbent assay with Geotrichum capitatum. J Clin Microbiol 2005;43:3925–31. These findings suggest that results obtained using this 6. Murashige N, Kami M, Kishi Y et al. False-positive results of Aspergillus enzyme-linked immunosorbent assays for a patient with gastrointestinal graft-versus-host disease taking assay should be treated with caution. a nutrient containing soybean protein. Clin Infect Dis 2005;40:333–4.

At present, the double-sandwich enzyme-linked immunosorbent Address for reprints: M Giacchino, Dipartimento di Biotecnologie Cellulari ed Ematologia, University La Sapienza of Rome, Via Benevento 6, assay (ELISA) is the diagnostic test most frequently used to 00161 Rome, Italy. Email: [email protected]

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Efficacy of environmental measures to decrease range of preventive measures. This requires commitment the risk of hospital-acquired aspergillosis in from members of the hospital administration department, patients hospitalised in haematology wards the engineering department, and members of the infection Berthelot P, Loulergue P, Raberin H et al. control committee. Although such an endeavor is costly and Clin Microbiol Infect 2006;12:738–44. labor-intensive, the money, time, and energy invested are largely justified by the benefits of preventing infections and The present study evaluated the effectiveness of a set of saving patient lives. 1. Alberti C, Bouakline A, Ribaud P et al. Relationship between environmental fungal preventive measures on the rate of invasive aspergillosis contamination and the incidence of invasive aspergillosis in hematology patients. (IA) in patients admitted to hematology wards. Although J Hosp Infect 2001;48:198–206. 2. Mahieu LM, De Dooy JJ, Van Laer FA et al. A prospective study on factors influencing the number of construction projects increased between aspergillus spore load in the air during renovation works in a neonatal intensive care unit. 1995 and 2001, the IA rate decreased significantly. This J Hosp Infect 2000;45:191–7. 3. Nolard N. Links between risks of aspergillosis and environmental contamination. suggests that a well-orchestrated team effort towards Review of the literature. Path Biol 1994;42:706–710. preventing IA is possible and can be effective. Address for reprints: P Berthelot, Infection Control Unit, Infectious Diseases Department, Infection Control Unit, University Hospital Invasive aspergillosis (IA) remains an important cause of of Saint-Etienne, 42055 Saint-Etienne cedex 2, France. death in patients with hematological malignancies. It has Email: [email protected] therefore been the target of various preventive measures in hospitalized, heavily immunosuppressed patients. Aspergillus Early onset endophthalmitis caused by spp spores are ubiquitous and can be present at high Aspergillus species following cataract surgery concentrations in dust particles, and environmental Callanan D, Scott IU, Murray TG et al. contamination is a recognized risk factor for the development Am J Ophthalmol 2006;142:509–11. of IA in hematological patients [1]. Furthermore, several reports have linked IA to hospital construction and This paper reports on a retrospective case series five renovation [2,3]. patients with early onset Aspergillus endophthalmitis The present study evaluated the effectiveness of a following cataract surgery. The authors recommend that multifaceted strategy aimed at decreasing the rate of IA Aspergillus should be considered in the differential in patients with hematological malignancies, during a period diagnosis of early onset postoperative endophthalmitis, of intensive construction work at a university hospital in with cultures obtained at presentation. France. During 1994–2001, a host of preventive measures were implemented: Postoperative endophthalmitis caused by Aspergillus spp is rare and is associated with poor outcomes. The authors of • Positive-pressure rooms. this study describe a consecutive series of five patients who • Strict hygiene practices. developed Aspergillus endophthalmitis following cataract • Dust control. surgery. The patients, who were treated by the authors • Partitioning of construction work areas from between 1992 and 2005, were identified from medical patient care areas. records. The mean time between surgery and presentation • Periodic environmental surveillance cultures. was 29 days. All five patients had decreased vision and eye pain, and three had flocculent material in the anterior The authors conducted a prospective survey to chamber. One patient was on oral corticosteroids and determine the number of IA cases on two hematology wards another was receiving chemotherapy. In terms of treatment, between 1993 and 2001. The results indicated that, the patients received intravitreal amphotericin B in although there were significant increases in the number combination with an oral azole, and one also received and risk level of hospital renovation projects between 1995 intravenous amphotericin B. Enucleation was performed in and 2001 (p<0.01), there was a decrease in the rate of IA three patients despite aggressive therapy. The remaining two between 1993 and 2001 (from 0.85% to 0.28%) and patients underwent vitrectomy and surgical debridement a significant decrease in the incidence of IA between and had poor visual outcomes (final visual acuity was 20/30 1993–1996 and 1997–2001 (p=0.02, Mann–Whitney in one patient and 20/200 in the other). U-test). The results of this study emphasize the importance There is now evidence to suggest that orally administered of a proactive team approach towards the prevention of IA voriconazole penetrates well into the aqueous and vitreous in high-risk patients. However, such results can only be humors. In one study, voriconazole achieved aqueous and maintained through continued efforts to implement the vitreous levels that exceeded the 90% minimum inhibitory

22 THE JOURNAL OF INVASIVE FUNGAL INFECTIONS VOL 1 NO 1 2007 CRYPTOCOCCOSIS

concentrations required for the treatment of infections In developing countries where the availability and cost of caused by Aspergillus and Candida spp. [1]. The safety of antifungals are problematic, fluconazole is frequently used as intravitreal voriconazole has also been recently investigated in a first line agent in the treatment of AIDS-associated an animal model [2]. Concentrations up to 25 mg/mL cryptococcal meningitis. In the present retrospective study, appeared to cause no retinal damage in treated rats. the authors report on the outcome of patients treated with So far, the clinical experience with voriconazole in one of two different doses of fluconazole (200 mg/day or the treatment of fungal endophthalmitis is promising. 400 mg/day) in South Africa. Subjects with HIV presenting Voriconazole alone or in combination with caspofungin has with a first episode of cryptococcal meningitis at a single been used successfully for the treatment of four of five secondary level hospital between January 1999 and patients with Candida endophthalmitis [3]. More recently, Decmber 2002 were identified by chart review. Between Sen et al. described their experience with intravitreal 1999 and April 2001, because of limited funds, patients voriconazole for the treatment of drug-resistant fungal were given low-dose fluconazole; patients with a poor endophthalmitis [4]. The infection was successfully eradicated prognosis were not offered therapy and were referred for in all five reported cases. Evisceration of the affected eye palliative care. A donation of fluconazole in April 2001 was avoided in one case. In another study, oral posaconazole allowed the standard dose to be administered after this time. was used to treat a woman with amphotericin-resistant None of the patients received antiretroviral therapy. Of Fusarium solani keratitis that progressed to invasive 205 subjects included in the study, 77 received low-dose endophthalmitis [5]. The patient exhibited a prompt response treatment and 128 received standard treatment. The rate and had good recovery of retinal function. The ocular of in-hospital mortality during first hospital admission penetration of posaconazole was confirmed by an aqueous tap. was high overall (25%) and was similar for the two doses. In conclusion, the new azoles constitute effective alternative Lack of antifungal treatment, lower level of consciousness, therapeutic agents in the treatment of fungal endophthalmitis. and a cerebrospinal fluid antigen titer >1000 were all 1. Hariprasad SM, Mieler WF, Holz ER et al. Determination of vitreous, aqueous, and plasma independent predictors of in-hospital mortality. According concentration of orally administered voriconazole in humans. Arch Ophthalmol 2004;122:42–7. to Kaplan–Meier analysis, the higher dose was not 2. Hua G, Pennesi M, Shah K et al. Safety of intravitreal voriconazole: electroretinographic associated with a survival benefit. Median survival was and histopathologic studies. Trans Am Ophthalmol Soc 2003;101:183–9. 3. Breit SM, Hariprasad SM, Mieler WF et al. Management of endogenous fungal 82 days with low-dose fluconazole and 76 days with endophthalmitis with voriconazole and caspofungin. Am J Ophthalmol 2005;139:135–40. standard-dose fluconazole. 4. Sen P, Gopal L, Sen PR. Intravitreal voriconazole for drug-resistant fungal endophthalmitis: case series. Retina 2006;26:935–9. There is evidence that resistance rates of Cryptococcus 5. Sponsel WE, Graybill JR, Nevarez HL et al. Ocular and systemic posaconazole neoformans to fluconazole in South Africa have been (SCH-56592) treatment of invasive Fusarium solani keratitis and endophthalmitis. Br J Ophthalmol 2002;86:829–30. increasing (from 0% in 1999 to 13% in 2004) [1]. Similar

Address for reprints: D Callanan, Texas Retina Associates, trends have been reported in other developing countries 1001 North Waldrop Drive, Suite 512, Arlington, TX 76012, USA. [2,3]. Heteroresistance to fluconazole has been observed Email: [email protected] among C. neoformans isolates, even where there has been no prior exposure to fluconazole [4]. In a recent study, Bicanic et al. investigated 32 episodes CRYPTOCOCCOSIS of relapsing cryptococcal meningitis among HIV-infected patients [5]. The authors found that 76% of culture- positive relapses were due to fluconazole-resistant isolates. Outcome of AIDS-associated cryptococcal Patients with drug-resistant infections had a 54% mortality meningitis initially treated with 200 mg/day rate at the 6-month follow-up, despite prolonged or 400 mg/day of fluconazole amphotericin B treatment. Schaars CF, Meintjes GA, Morroni C et al. The authors of the present paper report similar outcomes BMC Infect Dis 2006;6:118. with low and high doses of fluconazole. However, the outcome measures they used were length of hospital stay, This retrospective study compared two doses of in-hospital mortality, and degree of disability on discharge. fluconazole (200 mg/day and 400 mg/day) for the Relapse rates and post-treatment fluconazole susceptibility initial treatment of AIDS-associated cryptococcal were not assessed. meningitis in South Africa. Overall, in-hospital mortality Amphotericin B remains the agent of choice for the initial was high (25%). Kaplan–Meier analysis showed a similar treatment of cryptococcal meningitis in HIV patients. When length of survival at the two treatment doses (p=0.27). fluconazole is used in place of amphotericin B, high doses of fluconazole should be administered to maximize clinical and

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microbiological response rates and to minimize the sent to the National Health Laboratory Service Mycology emergence of azole resistance [6]. Reference Unit of the National Institute for Communicable 1. Pfaller MA, Diekema DJ, Rinaldi MG et al. Results from the ARTEMIS DISK Global Diseases (NICD; Johannesburg, South Africa) for species Antifungal Surveillance Study: a 6.5-year analysis of susceptibilities of Candida and other yeast species to fluconazole and voriconazole by standardized disk diffusion testing. confirmation and serogrouping using canavanine- J Clin Microbiol 2005;43:5848–59. glycine–bromthymol blue agar. The species of the majority 2. Sar B, Monchy D, Vann M et al. Increasing in vitro resistance to fluconazole in Cryptococcus neoformans Cambodian isolates: April 200 to March 2002. of C gattii isolates and a subset of non-gattii Cryptococcus J Antimicrob Chemother 2004;54:563–5. 3. Datta K, Jain N, Sethi S et al. Fluconazole and itraconazole susceptibility of clinical isolates isolates was confirmed by serotyping using the Crypto-Chek of Cryptococcus neoformans at a tertiary care centre in India: a need for care. kit (Mitzubishi Kagaku Iatron, Tokyo, Japan) at the J Antimicrob Chemother 2003;52:683–6. 4. Mondon P, Petter R, Amalfitano G, et al. Heteroresistance to fluconazole and voriconazole Centers for Disease Control and Prevention in Cryptococcus neoformans. Antimicrob Agents Chemother 1999;43:1856–61. Reference Unit (Atlanta, GA, USA); minimal inhibitory 5. Bicanic T, Harrison T, Niepieklo A et al. Symptomatic relapse of HIVassociated cryptococcal meningitis after initial fluconazole monotherapy: the role of fluconazole resistance and concentration (MIC) testing was also performed here using immune reconstitution. Clin Infect Dis 2006;43:1069–73. two different methods. 6. Hamill RJ. Free fluconazole for cryptococcal meningitis: too little of a good thing? Clin Infect Dis 2006;43:1074–6. There were 2753 cases of cryptococcosis over the

Address for reprints: T Bicanic, Desmond Tutu HIV Centre, Wehner study period. Of 1912 viable isolates received by the and Beit Building North, Institute of Infectious Disease and Molecular NICD, 2.4% were identified as C gattii. All isolates had Medicine, University of Cape Town Faculty of Health Sciences, low MICs to all antifungals tested (fluconazole, itraconazole, Anzio Road, Observatory 7925, Cape Town, South Africa. and voriconazole).The majority of C. gattii-infected patients Email: [email protected] (61%) had HIV infection, and most presented with symptoms of meningitis (headache 76%; stiff neck 67%; Cryptococcus gattii infection: characteristics and and fever 54%). Over one-third of the patients with C gattii epidemiology of cases identified in a South African infection died during hospitalization for the index event. province with high HIV seroprevalence, 2002–2004 There were no significant differences between C gattii- Morgan J, McCarthy KM, Gould S et al; Gauteng infected patients and non-gattii Cryptococcus-infected Cryptococcal Surveillance Initiative Group patients in terms of demographic or clinical characteristics. Clin Infect Dis 2006;43:1077–80. The authors stress that their results probably underestimate the true prevalence of C gatti, given the This study describes the characteristics of patients with limitations of the diagnostic techniques available in this Cryptococcus gattii infection in an HIV-endemic area of geographic area. Indeed, a recent genotypic analysis of South Africa. Of the isolates tested, 2.4% were identified 176 cryptococcal isolates in Botswana and Malawi as C gattii. The majority of patients had HIV infection, found that 13.6% of the tested isolates were C gattii and the most common form of infection was meningitis. serotype C [1]. The clinical characteristics and outcome of patients with Initially, C gattii was thought to preferentially infect C gattii infection were similar to those infected with immunocompetent hosts. This theory was recently refuted in other Cryptococcus spp. an experimental murine model in which no difference in infection rate was observed in immunocompetent and Recent genotypic analyses revealed significant genetic immunodeficient mice [2]. The results of the present study differences within Cryptococcus neoformans isolates, which corroborate these findings. led to the pathogen being divided into two species: Routine speciation of Cryptococcus spp isolates for C neoformans (which includes C neoformans var brugii and detection of C gattii is not recommended because it has C neoformans var neoformans) and C gattii. The similar clinical characteristics to C neoformans. However, epidemiology of C gattii is not as well understood as that of given the concern for the tendency of C gattii to exhibit C neoformans. It has typically been reported from tropical higher MIC values, speciation should be considered in areas and subtropical areas, but it recently emerged as an that are endemic for C gattii when an adequate response to important pathogen in Vancouver (BC, Canada). The present therapy is not achieved. paper describes the characteristics of patients with C gattii 1. Litvintseva AP, Thakur R, Reller LB et al. Prevalence of clinical isolates of Cryptococcus gattii serotype C among patients with AIDS in sub-Saharan Africa. J Infect Dis infection in a South African province. 2005;192:888–92. Cryptococcosis cases were identified by population- 2. Capilla J, Maffei CM, Clemons KV et al. Experimental systemic infection with Cryptococcus neoformans var grubii and Cryptococcus gattii in normal and immunodeficient mice. based surveillance from March 2002 to March 2004, in Med Mycol 2006;44:601–10. which surveillance officers collected data from laboratories Address for reprints: ME Brandt, Mycotic Diseases Branch, Centers for and medical records on a weekly basis. Isolates identified as Disease Control and Prevention, 1600 Clifton Road, Mailstop G-11, Cryptococcus spp isolates at the originating institutions were Atlanta, GA 30333, USA. Email: [email protected]

24 THE JOURNAL OF INVASIVE FUNGAL INFECTIONS VOL 1 NO 1 2007 LESS COMMON MYCOSES

LESS COMMON MYCOSES R mucilaginosa in healthcare settings. Perniola et al. recently reported an outbreak of bloodstream infections due to R mucilaginosa in a neonatal intensive care unit in Italy [2]. Epidemiology and outcome of Rhodotorula Birth weight, gestational age, duration of parenteral nutrition, in a tertiary care hospital duration of antibiotic therapy, and prophylactic administration Lunardi LW, Aquino VR, Zimerman RA et al. of fluconazole were all risk factors for infection. Clin Infect Dis 2006;43:e60–3. In such outbreak settings, additional epidemiological data are usually required for a complete investigation. Pulsed-field The results of this retrospective study indicate that gel electrophoresis was recently used for the first time to cancer patients, patients receiving corticosteroids or analyze genetic similarities between R mucilaginosa clinical other immunosuppressive therapy, patients with central isolates [3]. venous catheters, and patients receiving broad-spectrum Although less frequent than candidiasis, Rhodotorula spp antibiotic therapy are most susceptible to Rhodotorula should be considered alongside Candida spp in the differential fungemia. Occasionally, immediate catheter removal diagnosis of fungemic patients with intravascular catheters. can be avoided. Conversely, catheter removal is Given the potential for nosocomial dissemination, infection sometimes sufficient to eradicate the infection. control practices should be emphasized in such patients. 1. Kiehn TE, Gorey E, Brown AE et al. Sepsis due to Rhodotorula related to use of indwelling central venous catheters. Clin Infect Dis 1992;14:841–6. Rhodotorula is a genus of yeasts that can be found in air, soil, 2. Perniola R, Faneschi ML, Manso E et al. Rhodotorula mucilaginosa outbreak in neonatal salt water, fresh water, and dairy products. Although intensive care unit: microbiological features, clinical presentation, and analysis of related variables. Eur J Clin Microbiol Infect Dis 2006;25:193–6. traditionally considered to be a saprophyte that can colonize 3. Saracli MA, Sener K, Gonlum A et al. Genotyping of clinical Rhodotorula mucilaginosa plants, humans, and other mammals, it has recently emerged isolates by pulsed field gel electrophoresis. Mycoses 2003;46:487–91. as an opportunistic pathogen in immunocompromised hosts. Address for reprints: LZ Goldani, Unidade de Infectologia, Hospital de In the present retrospective study, the authors reviewed Clínicas de Porto Alegre, Rua Ramiro Barcelos 2350, 90035-003 Porto the medical records of patients at a tertiary care hospital in Alegre, RS, Brazil. Email: [email protected] southern Brazil over a 4-year period to investigate the risk factors for, and treatment of, Rhodotorula fungemia. Seven Human and canine pulmonary blastomycosis, patients with Rhodotorula mucilaginosa bloodstream North Carolina, 2001-2002 infections were identified; the rate was 0.056 episodes per MacDonald PD, Langley RL, Gerkin SR et al. 1000 hospital admissions. All seven patients had a central Emerg Infect Dis 2006;12:1242–4. venous catheter; four patients (57%) had solid tumors and been exposed to cytotoxic drugs; three patients (43%) had The present report described a cluster of 8 human leukemia and been exposed to corticosteroids and cytotoxic and 4 canine cases of pulmonary blastomycosis in drugs; six patients (86%) were neutropenic and had been North Carolina (USA) during 2001–2002. Outbreaks exposed to broad-spectrum antibiotics; and two patients of this disease are difficult to study because of delayed (28%) had been taking prophylatic fluconazole. In terms of diagnosis, difficulty isolating Blastomyces dermatitidis treatment, all seven patients had their catheter removed, and in nature, and the lack of a test with high specificity five also received antifungal therapy (amphotericin B [AmB] and sensitivity for assessing exposure. plus 5-flucytosine n=2; AmB n=2; fluconazole n=1; and voriconazole following AmB n=1). The two patients treated The epidemiology of blastomycosis is not entirely clear, largely only by catheter removal survived. However, three of the five due to difficulties in diagnostic testing. Most of the available patients treated with antifungal therapy plus catheter information is based on reports of clinical infection in humans removal died within 10 days of incident sample culture. and dogs in high prevalence areas. In the present study, The largest series of cases of Rhodotorula fungemia was MacDonald et al. described a cluster of eight human and four reported in 1992 at the Memorial Sloan-Kettering Cancer canine cases of pulmonary blastomycosis in a rural community Center (New York, NY, USA) [1]. This paper reported on in North Carolina (USA) during 2001–2002. Although the 23 patients who developed catheter-related Rhodotorula epidemic curve was consistent with ongoing exposure, no sepsis between 1985 and 1989. In contrast to the study by common source for human and canine exposure was identified. Lunardi and colleagues, all 23 patients survived, without Although most cases of blastomycosis are concentrated recurrence of the infection. in North America, the disease has been occasionally reported In addition to sporadic infections in critically ill patients in Africa [1], Central and South America [2], India [3], and with intravascular catheters, there have been outbreaks of the Middle East [4].

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In a case–control study performed by the US Centers for amphibian, reptile, and bat droppings. Most human cases of Disease Control and Prevention (CDC) in Missouri, 93 cases have been reported from Africa, South of blastomycosis in humans were studied [5]. Black race and America, and tropical Asia. The most common form of a history of pneumonia were the only risk factors for infection in humans is subcutaneous chronic zygomycosis [1]. infection. However, blastomycosis in dogs has been However, systemic infections have occasionally been reported. associated with residence in proximity to a waterway and In this report, the authors describe a 61-year-old patient exposure to an excavation site [6]. with gastrointestinal basidiobolomycosis. The man presented In an attempt to shed light on the molecular with progressive left abdominal pain and constipation. epidemiology of blastomycosis, McCullough et al. examined Colonoscopy an obstructing colonic mass, and a the genetic diversity of 59 Blastomyces dermatitidis isolates hemicolectomy was performed. Histology showed from various endemic areas in North America, India, and inflammation, possibly caused by a fungal or parasitic Africa [7]. Using a polymerase chain reaction-based typing infection, but a specific organism was not identified. A system and restriction fragment length polymorphism computed tomography (CT) scan was performed a few analysis, isolates were classified into three major groups. weeks after the operation because of abdominal discomfort, The authors showed that in one outbreak, the soil isolates and showed a liver mass 6 cm in diameter. Treatment with did not correspond to the clinical isolates. In addition, more metronidazole, directed at an amoebic liver abcess, was than one strain was found in environmental and clinical unsuccessful, but subsequent treatment with fluconazole samples. As demonstrated by this and by previous studies, resulted in a small decrease in the size of the abcess. The environmental testing is of limited value in identifying the patient developed marked eosinophilia (27.7%), and so source of clinical outbreaks. a liver biopsy was performed and the patient was referred to 1. Klein BS, Aizenstein BD, Hogan LH. African strains of Blastomyces dermatitidis that a university hospital. A repeat CT scan showed that the liver do not express surface adhesin WI-1. Infect Immun 1997;65:1505–9. 2. Tenenbaum MJ, Greenspan J, Kerkering TM. Blastomycosis. Crit Rev Microbiol mass had grown (9 cm diameter). Colon and liver biopsy 1982;9:139–63. samples showed extensive necrosis and histiocytes, 3. Randhawa HS, Chaturvedi VP, Kini S et al. Blastomyces dermatitidis in bats: first report of its isolation from the liver of Rhinopoma hardwickei hardwickei Gray. Sabouraudia multinucleated giant cells, and numerous eosinophils. In 1985;23:69–76. Grocott-stained sections, unusually large hyphae could be 4. Kingston M, El-Mishad MM, Ali MA. Blastomycosis in Saudi Arabia. Am J Trop Med Hyg 1980;29:464–6. seen, and these were surrounded by strongly eosinophilic 5. Cano MV, Ponce-de-Leon GF, Tippen S et al. Blastomycosis in Missouri: epidemiology material in haematoxylin- and eosin-stained sections and risk factors for endemic disease. Epidemiol Infect 2003;131:907–14. 6. Baumgardner DJ, Paretsky DP, Yopp AC. The epidemiology of blastomycosis in dogs: (Splendore–Hoeppli phenomenon). Based on these findings, north central Wisconsin, USA. J Med Vet Mycol 1995;33:171–6. a diagnosis of Basidiobolus spp infection was made. 7. McCullough MJ, DiSalvo AF, Clemons KV et al. Molecular Epidemiology of Blastomyces dermatitidis. Clin Infect Dis 2000;30:328–35. Although itraconazole remains the antifungal agent of choice, this was contraindicated because of renal Address for reprints: PDM MacDonald, Department of Epidemiology, North Carolina Center for Public Health Preparedness, North Carolina insufficiency, and so amphotericin B was used. The patient Institute for Public Health, CB #8165, Chapel Hill, NC 27599, USA. developed multi-organ failure and died a few days later. Email: [email protected]. After autopsy, was cultured from liver, gallbladder, and colon. A fatal pseudo-tumour: disseminated Gastrointestinal basidiobolomycosis has mostly been basidiobolomycosis reported in children. The US Centers for Disease Control and van der Berk GE, Noorduyn LA, van Ketel RJ et al. Prevention has conducted an epidemiological investigation BMC Infect Dis 2006;6:140. of a cluster of seven cases of gastrointestinal basidio- bolomycosis in adult patients from Arizona [2]. The infection This case report describes a 61-year-old man with can involve the colon, rectum, stomach, duodenum, liver, gastrointestinal basidiobolomycosis that manifested as and pancreas. Potential risk factors included prior ranitidine an obstructing colonic tumor and a hepatic mass. Despite use and longer residence in Arizona. In addition, hemicolectomy and treatment with fluconazole and histopathological analysis of six cases of gastrointestinal amphotericin B, the patient developed multi-organ failure basidiobolomycosis in Arizona has been conducted [3]. and died. This is only the second reported case of fatal There was marked mural thickening and fibrosis in the gastrointestinal basidiobolomycosis. gastric and intestinal specimens when compared with controls. Splendore–Hoeppli phenomenon was seen. Colonic Basidiobolomycosis is caused by a rare fungus of the perforation was found in two cases. Zygomyecetes class, Basidiobolus ranarum. Basidiobolus is Radiographic findings in gastrointestinal basidio- a saprophytic filamentous fungus that can be grown from bolomycosis may mimic Crohn’s disease [4]. Common

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features include concentric colonic wall thickening, • Differential induction of target cell death (infliximab perivisceral inflammation, fistulization, perforation, and induces apoptosis of monocytes and lymphocytes, abscess formation. whereas etanercept does not). The treatment of basidiobolomycosis is difficult. More • Differential inhibition of TNF-α signaling (infliximab studies are needed to determine the susceptibility of this rare binds to both soluble and transmembrane TNF-α, fungus to the new generation azoles and echinocandins. whereas etanercept binds only to soluble TNF-α). 1. Sugar AM. Agents of and related species. In Mandell GL, Bennett JE, • Differential net blockade of TNF-α bioactivity (rapid Dolin R (editors). Mandell, Douglas and Bennetts’s Principles and Practice of Infectious Diseases 6th edition. Elsevier, Philadelphia, PA, USA. 2005:2973–84. and irreversible binding of infliximab to TNF-α vs. release 2. Lyon GM, Smilack JD, Komatsu KK et al. Gastrointestinal basidiobolomycosis in Arizona: clinical and epidemiological characteristics and review of the literature. Clin Infect Dis of TNF-α 10 min after etanercept administration). 2001;32:1448–55. 3. Yousef OM, Smilack JD, Kerr DM et al. Gastrointestinal basidiobolomycosis. Morphologic findings in a cluster of six cases. Am J Clin Pathol 1999;112:610–6. There are limited available data regarding the newest 4. Nguyen BD. CT features of basidiobolomycosis with gastrointestinal and urinary involvement. AJR Am J Roentgenol 2000;174:878–9. agent, adalimumab. Reactivation of latent tuberculosis has been reported with adalimumab in a dose-related response [4]. Address for reprints: GE van den Berk, Department of Internal Medicine, Division of Infectious Diseases, Tropical Medicine and AIDS, Academic Since the clinical use of TNF blockers is expected to Medical Center, Amsterdam, the Netherlands. increase, the continued monitoring and reporting of adverse Email: [email protected] events is crucial to ensure patient safety and to reduce morbidity and mortality associated with opportunistic infections in these high-risk patients. 1. Wallis RS, Broder MS, Wong JY et al. Reactivation of latent granulomatous infections THERAPEUTICS by infliximab. Clin Infect Dis 2005;41:S194–8. 2. Wallis RS, Broder MS, Wong JY et al. Granulomatous infectious diseases associated with tumor necrosis factor antagonists. Clin Infect Dis 2004;38:1261–5. 3. Ehlers S. Tumor necrosis factor and its blockade in granulomatous infections: differential Pulmonary adverse events of anti-tumor modes of action of infliximab and etanercept? Clin Infect Dis 2005;41:S199–203. necrosis factor-α therapy 4. Wallis RS, Broder MS, Wong JY et al. Granulomatous infectious diseases associated with tumor necrosis factor antagonists. Clin Infect Dis 2004;38:1261–5. Mutlu GM, Mutlu EA, Bellmeyer A et al. Am J Med 2006;119:639–46. Address for reprints: GM Mutlu, Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, 240 East Huron Street, McGaw Building, Room 2342, Chicago, IL 60611, USA. This paper provides a review of the available data on the Email: [email protected] risk of pulmonary infections following anti-tumor necrosis factor-α (TNF-α) antibody therapy. Increased awareness among prescribing physicians and careful patient selection New agents for the treatment of fungal infections: for anti-TNF-α therapy will help to prevent and allow clinical efficacy and gaps in coverage early detection of these serious infections. Spanakis EK, Aperis G, Mylonakis E. Clin Infect Dis 2006;43:1060–8. The authors of this paper provide a useful review of the role α α of tumor necrosis factor- (TNF- ) in the initiation and New treatment options are now available for the various maintenance of the inflammatory response to various fungal infections encountered in the clinical setting. This α infections, the use of anti-TNF- antibody therapy in review of the data on the clinical efficacy of these agents diseases such as rheumatoid arthritis, and the risk of reports that the use of voriconazole as a primary treatment pulmonary infections following therapy with these agents. for invasive aspergillosis is increasing, posaconazole has Although many patients continue to benefit dramatically a broad anti-fungal spectrum, and the echinocandins are α α from anti-TNF- therapy, TNF- blockade compromises host effective against most Candida spp. resistance to infections, particularly granulomatous diseases [1]. The authors make an important point in the present The antifungal armamentarium has recently expanded to review: TNF-α antagonists differ in terms of the risks they pose include several new agents for the treatment of various for reactivation of latent granulomatous infections. Indeed, fungal infections. In the present review, the authors provide between January 1998 and September 2002, the US Food and a summary of the trials that have investigated the efficacy Drug Administration received reports of 255 granulomatous of the new antifungal agents (newer triazoles and infections following infliximab therapy and 68 infections echinocandins) in the clinical setting. following treatment with etanercept (129 vs. 60 infections per Whereas voriconazole is being increasingly used for the 100 000 treated patients, relative risk 2.1) [2]. Three treatment of proven or suspected invasive aspergillosis (IA), hypotheses were postulated to explain this disparity [3]: echinocandins are very helpful in the treatment of Candida

THE JOURNAL OF INVASIVE FUNGAL INFECTIONS VOL 1 NO 1 2007 27 CLINICAL REVIEWS

spp, particularly of azole-resistant isolates. The strength of Prospective study of amphotericin B posaconazole lies in its broad activity against filamentous formulations in immunocompromised fungi, including zygomycetes. patients in 4 European countries In addition to the studies evaluated in this review, new Ullmann AJ, Sanz MA, Tramarin A et al. data have been recently reported. Two randomized trials Clin Infect Dis 2006;43:e29–38. recently examined treatment options for invasive candidiasis [1,2]. The first study compared caspofungin at a dose of This prospective study investigated the outcomes of 50 mg/day after a loading dose of 70 mg on day 1 with adult patients receiving amphotericin B deoxycholate two doses of micafungin (100 mg/day and 150 mg/day) in (AmB-d) or lipid formulations of AmB in 20 European adult patients with invasive candidiasis [1]. Micafungin hospitals. The authors recommend that newer, less toxic was not inferior to caspofungin in terms of efficacy or safety, antifungals should be used in place of AmB to improve and no advantage was seen with higher doses of caspofungin. treatment outcomes. The second study compared micafungin with liposomal amphotericin B (L-AmB) in pediatric patients with invasive Since its first introduction in 1959, amphotericin B candidiasis [2], and reported that micafungin was as deoxycholate (AmB-d) has successfully been used for the effective as L-AmB in the overall population. treatment of various fungal infections. However, a number Treatment options for IA have also recently been of studies have shown that AmB-d associated with evaluated [3,4]. When compared with high-dose lipid significant nephrotoxicity, which sometimes precludes its formulations of AmB, posaconazole appeared to be more use. Lipid formulations of AmB are now available, and these efficacious and safer as salvage therapy for IA in patients have proved to be less nephrotoxic than AmB-d [1]. with hematologic malignancy [3]. In view of preliminary The aim of this longitudinal, prospective, observational evidence suggesting benefit from the use of combination study was to compare the outcomes of patients treated with therapy with voriconazole plus caspofungin in IA, Raad et al. different formulations of AmB in 20 European centers (four concluded that the combination of voriconazole and in Italy, four in the UK, six in Germany, and six in Spain). caspofungin is an effective treatment strategy in patients Of 418 patients studied, 62% initially received AmB-d, with hematologic malignancy and IA [4]. 27% received liposomal AmB, and 11% received other lipid Finally, in two different studies, micafungin-based formulations of AmB. At baseline, 390 patients had normal antifungal combinations were found to be safe and kidney function, and 57% of these went on to develop reasonably efficacious in the treatment of IA [5,6]. nephrotoxicity. Patients with nephrotoxicity had a higher 1. Betts RF, Rotstein C, Talwar D et al. Comparison of micafungin and caspofungin for mortality rate and a longer hospital stay than patients who candidemia or invasive candidiasis [Abstract M-1308a]. Presented at The 46th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, did not develop nephrotoxicity. Duration of therapy and CA, USA, September 27–30, 2006. choice of formulation used as initial therapy were predictors 2. Arrieta AC, Telles Filho F, Berezin E et al, for the Micafungin Invasive Candidiasis Study Group. A randomized, double-blind trial comparing micafungin and liposomal of the development of nephrotoxicity; AmB-d was a stronger amphotericin B in pediatric patients with invasive candidiasis [Abstract M-1308b]. Presented at The 46th Annual Interscience Conference on Antimicrobial Agents predictor than the other formulations. Of the patients and Chemotherapy, San Francisco, CA, USA, September 27–30, 2006. initially treated with AmB-d, 36% had switched to lipid 3. Raad II, Hanna H, Boktour M et al. Posaconazole compared to high-dose lipid formulations of amphotericin B as salvage therapy for invasive aspergillosis in patients formulations, primarily because of increased serum creatinine with hematologic malignancy [Abstract M-874]. Presented at The 46th Annual levels (in 45.7% of patients) or other AMB-attributable Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, CA, USA, September 27–30, 2006. adverse events (in 41.3% of patients). 4. Raad II, Hanna H, Boktour M et al. The combination of caspofungin and voriconazole For several decades, and in the absence of therapeutic as primary and salvage therapy of invasive aspergillosis in hematologic malignancy patients [Abstract M-889]. Presented at The 46th Annual Interscience Conference options for azole-resistant fungal infections, AmB-d on Antimicrobial Agents and Chemotherapy, San Francisco, CA, USA, September 27–30, 2006. was considered to be the “gold standard” antifungal 5. Kontoyiannis DP, Ratanatharathorn V, Van Burik J et al. Micafungin alone or in agent. However, three lipid formulations of AmB have combination with other licensed antifungal therapy in bone marrow transplant recipients with invasive aspergillosis [Abstract M-878]. Presented at The 46th Annual Interscience been developed: Conference on Antimicrobial Agents and Chemotherapy, San Francisco, CA, USA, September 27–30, 2006. 6. Flynn PM, Seibel N, Arrieta AC et al. Treatment of invasive aspergillosis in pediatric • AmB lipid complex (Abelcet®, the Liposome Company, patients with micafungin alone or in combination with other systemic antifungal agents [Abstract M-891]. Presented at The 46th Annual Interscience Conference on Inc., Princeton, NJ, USA). Antimicrobial Agents and Chemotherapy, San Francisco, CA, USA, ® September 27–30, 2006. • Liposomal AmB (Ambisome , Fujisawa Healthcare, Inc., Deerfield, IL, USA, and Gilead Science). Address for reprints: EK Mylonakis, Massachusetts General Hospital, • AmB cholesteryl sulfate complex (Amphotec™, Sequus Gray-Jackson 504, 55 Fruit Street, Boston, MA 02114, USA. Email: [email protected] Pharmaceuticals, Inc., Menlo Park, CA, USA).

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In vitro and in vivo evidence has demonstrated that these Asia in collaboration with the World Health Organization, agents are at least as effective as AmB-d in the treatment of to evaluate the effectiveness of a short course of topical invasive mycoses. However, the main advantage conferred ointments to patients with corneal abrasions in the by the lipid formulations is a reduced risk for nephrotoxicity prevention of ulceration. compared with traditional AMB-d therapy. In the first study, 115 patients with corneal abrasions More recently, voriconazole has proved to be effective in were treated with 1% chloramphenicol ointment three times the treatment of invasive aspergillosis. In addition, daily for 3 days [1]. The study was conducted in Bhutan, echinocandins have been increasingly used for Candida where 98% of all culture-positive corneal ulcers are caused infections and as empirical therapy in patients with by bacterial pathogens. None of the patients developed neutropenic fever. However, when compared with AmB, corneal ulcerations, and all patients healed uneventfully. gaps in treatment coverage still exist in these new agents, It was concluded that antibiotic ointments can successfully mainly against zygomycetes. The newest azole, posaconazole, prevent bacterial corneal ulcers. is active against both Aspergillus spp and zygomycetes. The present prospective study was conducted in Burma, So far, in vitro and in vivo data supporting the use of where two-thirds of all corneal ulcerations are caused by posaconazole have been promising. fungi. Individuals from three selected villages (n=16 987 in AmB-d is affordable and widely available. Although it is total) were followed for 1 year by village health workers less likely to be nephrotoxic in neonates than in adults, it can (VHW) trained to identify patients with post-traumatic be tolerated in brief, low-dose courses in adults. Therefore, corneal abrasions and to administer antibacterial and AmB-d is still recommended as first-line therapy in AIDS- antifungal ointments (1% chloramphenicol and 1% associated cryptococcal meningitis. It can also be given clotrimazole) to those who met the eligibility criteria. Of the intrathecally in the setting of . With the 273 individuals who presented to the VHS with an ocular advent of all the antifungal agents described above, the injury during the study, 126 had a corneal abrasion. All place of AmB-d in the treatment of invasive mycoses is 126 received the preventive treatment three times daily for being continuously redefined. 3 days, and all tolerated the ointments well and had an 1. Cannon JP, Garey KW, Danziger LH. A prospective and retrospective analysis uneventful recovery. The authors concluded that bacterial of the nephrotoxicity and efficacy of lipid-based amphotericin B formulations. Pharmacotherapy 2001;21:1107–14. and fungal ulcers can be prevented by treating potential sites of infection. Address for reprints: AJ Ullmann, Klinikum Johannes Gutenberg- Universität, III. Medizinische Klinik und Poliklinik, Langenbeckstrasse 1, In the third study, 374 patients with corneal abrasions 55101 Mainz, Germany. Email: [email protected] were randomized to receive 1% chloramphenicol and 1% clotrimazole ointments (n=169) or 1% chloramphenicol and Corneal ulceration in South East Asia. placebo ointments (n=205) [2]. The site of this third study II: a strategy for the prevention of fungal was India, where fungi account for 50% of corneal keratitis at the village level in Burma ulcerations. The vast majority of patients (n=368) healed Maung N, Thant CC, Srinivasan M et al. without sequelae. Interestingly, bacterial and fungal ulcers Br J Ophthalmol 2006;90:968–70. were prevented in both groups of patients. The investigators concluded that antibacterial ointments can prevent bacterial The authors of this study evaluated the effectiveness and fungal ulcers, and that antifungal ointments are of antibiotic and antifungal ointments in the prevention apparently unnecessary. of corneal ulcers in Burmese patients with traumatic Therefore, simple preventive measures can be very corneal abrasions. All 126 patients included in the study effective in preventing corneal ulcers in developing countries. 1. Getshen K, Srinivasan M, Upadhyay MP et al. Corneal ulceration in South East Asia. tolerated the ointments well and healed uneventfully. I: a model for the prevention of bacterial ulcers at the village level in rural Bhutan. This preventive strategy is effective and easy to Br J Ophthalmol 2006;90:276–8. 2. Srinivasan M, Upadhyay MP, Priyadarsini B et al. Corneal ulceration in south-east Asia III: implement in developing countries. prevention of fungal keratitis at the village level in south India using topical antibiotics. Br J Ophthalmol 2006;90:1472–5.

Corneal ulceration is one of the most common causes of Address for reprints: JP Whitcher, Francis I Proctor Foundation, UCSF preventable blindness in South East Asia. The present study Box 0944, 95 Kirkham Street, San Francisco, CA 94143-0944, USA. was the second of three studies, conducted in South East Email; [email protected]

THE JOURNAL OF INVASIVE FUNGAL INFECTIONS VOL 1 NO 1 2007 29 46th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC)

San Francisco, CA, USA, September 27–30, 2006

Zeina A Kanafani

MEETING REPORT Division of Infectious Diseases, Duke University Medical Center, Durham, NC, USA

The 2006 Interscience Conference on Antimicrobial Agents were caused by non-albicans Candida spp (63% in the and Chemotherapy (ICAAC) program covered many aspects micafungin arm and 70% in the L-AmB arm). Micafungin of clinical mycology, including recent clinical trials, new and was as effective as L-AmB in the overall population (72.9% established antifungal agents, diagnostic laboratory testing, vs. 76.0%). In addition, micafungin and L-AmB were equally and antifungal susceptibility. This review will provide a efficacious in neutropenic patients (85.3% vs. 76.9%), patients summary of the key abstracts on clinical mycology presented aged <2 years (80.8% vs. 77.4%), and in premature infants at the meeting. (70.0% vs. 66.7%). To date, this is the largest trial in pediatric patients with invasive candidiasis, and suggests Management of invasive fungal infections that micafungin is an effective alternative to L-AmB for the Invasive candidiasis treatment of this infection. Two randomized trials examined treatment options for invasive candidiasis [1,2]. The first was a randomized Invasive aspergillosis double-blind study that compared caspofungin (70 mg Treatment options for invasive aspergillosis were evaluated loading dose, followed by 50 mg/day) with two doses of in several presentations [3,4]. Raad et al. conducted a micafungin (100 mg/day and 150 mg/day) in adult patients comparative, retrospective cohort study comparing with invasive candidiasis [1]. A total of 593 patients were posaconazole with high-dose lipid formulations of AmB as included in the intent-to-treat population (192, 199, and salvage therapy for invasive aspergillosis (IA) in patients with 202 patients in the caspofungin, micafungin [100 mg/day], hematological malignancies [3]. Patients received posaconazole and micafungin [150 mg/day], respectively). The primary (n=51) or high-dose lipid formulations of AmB (n=49; L-AmB endpoint was the clinical and mycological response at the or AmB lipid complex at doses of ≥7.5 mg/kg/day). Risk end of therapy. Overall response rates were similar for the factors (age, underlying malignancy, bone marrow three groups (71.4%, 73.9%, and 70.9%, respectively). transplantation, duration of neutropenia, immunosuppressant Success rates were not significantly different across the use, graft-versus-host disease) were similar in the two various Candida spp. All three treatments were equally well groups. The response rate to salvage therapy was significantly tolerated. This study is the first trial to directly compare the better with posaconazole than with lipid formulations of efficacy of two echinocandins in the treatment of invasive AMB (39% vs. 8%; p≤0.001). Mortalities that could be candidiasis. Micafungin was found to be non-inferior to attributed to aspergillosis were lower in the posaconazole caspofungin in terms of efficacy. Higher doses of micafungin group (at a rate of 39% compared with 63% in those who did not provide any additional benefit. received AMB; p=0.02). Posaconazole treatment was the Micafungin was also compared with liposomal only factor that was significantly associated with improved amphotericin B (L-AmB) in pediatric patients with invasive outcome (odds ratio [OR] 8.85, 95% confidence interval candidiasis [2]. The analysis included 98 patients who had [CI] 2.64–29.41). Higher rates of hepatotoxicity and culture-proven invasive candidiasis and had been randomized nephrotoxicity were observed with high-dose lipid to receive one of the study drugs (2 mg/kg/day micofungin, formulations of AMB compared with posaconazole. Thus the n=48; 3 mg/kg/day L-AmB, n=50). The majority of cases authors concluded that posaconazole appears to be more

30 THE JOURNAL OF INVASIVE FUNGAL INFECTIONS VOL 1 NO 1 2007 THE EUROPEAN SOCIETY OF CARDIOLOGY ANNUAL MEETING 2005

efficacious and safer than high-dose lipid formulations of invasive fungal infection compared with placebo, but no AMB as salvage therapy in IA. survival benefit was observed (B1 evidence level). In view of the preliminary evidence suggesting a benefit One of the concerns surrounding the widespread use of with the use of voriconazole/caspofungin combination therapy antifungal prophylaxis is the development of azole resistance. in IA, Raad et al. described their experience at the MD This was addressed as part of the analysis of two studies that Anderson Cancer Center (Houston, TX, USA) in patients with compared posaconazole with fluconazole or itraconazole for hematological malignancies [4]. Therapy was classified as prophylaxis in patients with acute myelogenous leukemia either primary (n=65) or salvage (n=69). Clinical characteristics (AML; n=1202) [8]. The distribution and susceptibilities of and outcomes were obtained for patients who received Candida isolates were assessed at baseline and at the end voriconazole alone, caspofungin alone, and voriconazole plus of therapy. The investigators found that the shift to caspofungin. In patients receiving primary therapy for IA, non-albicans species and the development of azole resistance response rates were better with combination therapy than were uncommon. Minimum inhibitory concentrations (MICs) with either voriconazole or caspofungin alone (50%, 19%, were increased for two C albicans isolates and 14 C glabrata and 30%, respectively; p≤0.03). Among the patients receiving isolates. Breakthrough Candida infections occurred in only salvage therapy, those who received combination therapy had 11 patients (in four patients while they were receiving a lower mortality rate than those who received caspofungin prophylaxis and in seven others after end of therapy). Eight alone. These findings suggest that the combination of of these breakthrough infections were due to C glabrata. voriconazole plus caspofungin is an effective treatment Therefore, the use of antifungal prophylaxis selected for strategy in patients with hematological malignancies and IA. azole resistance and for non-susceptible Candida spp to a Results were presented from two studies that evaluated limited extent only. the use of micafungin as monotherapy or as a combination In a small, randomized trial in patients with AML, therapy with other antifungal agents in the treatment of IA voriconazole was compared with placebo for prophylaxis [5,6]. In the first study, 98 adult bone marrow transplant during induction chemotherapy [9]. Ten patients were recipients were treated with micafungin, either alone (n=8) randomized to voriconazole and 15 to placebo. By day 21, or in combination with other antifungal therapy (n=90) [5]. none of the patients on voriconazole and five patients on A partial or complete response was seen in 22 patients who placebo had developed lung infiltrates (p=0.04). After were on combination therapy (24%) and in three patients 4 weeks of follow-up, no patients in the voriconazole arm who received micafungin alone (38%). The second study and four patients in the placebo arm had developed chronic investigated the efficacy of micafungin-based regimens in disseminated candidiasis (p=0.07). These are promising 58 pediatric patients with IA [6]. The majority of patients results and call for larger studies to corroborate the value of received micafungin in combination with L-AmB (n=47). voriconazole as a prophylactic agent in neutropenic patients Only two patients received micafungin alone. Nine patients with AML. exhibited a complete response to therapy (16%), and a Another randomized trial studied the efficacy of further 17 patients had a partial response (29%). In both aerosolized L-AmB as a prophylactic regimen against IA studies, micafungin was well tolerated. It can be concluded in patients with prolonged neutropenia [10]. The analysis that micafungin-based antifungal combinations are safe and included 271 patients with 406 neutropenic episodes; reasonably efficacious in the treatment of IA. 139 patients were randomized to inhaled L-AmB via an Adaptive Aerosol Delivery system (AAD®, Respironics Antifungal prophylaxis Respiratory Drug Delivery [UK] Ltd, Bognor Regis, West Cornely et al. performed a large systemic analysis of Sussex, UK) twice weekly for 30 min each, and 132 patients 15 277 episodes of invasive fungal infection to evaluate the were randomized to receive placebo. The rate of proven or use of antifungal prophylaxis in cancer patients [7]. Seventy- probable IA was 4% in the L-AmB arm and 14% in the six randomized, controlled trials were identified. Antifungal placebo arm (p=0.003). No difference in mortality rates prophylaxis regimens included itraconazole, fluconazole, between the two groups was detected. Therefore, inhaled and posaconazole. It was found that prophylaxis with L-AmB can be considered a viable alternative to traditional fluconazole or posaconazole resulted in decreased mortality antifungal prophylaxis in patients with prolonged neutropenia. rate and breakthrough invasive fungal infections in stem cell transplant patients (A1 evidence level). Reduced mortality Emerging fungal infections rates were also seen with posaconazole prophylaxis in Several presentations dealt with the recently described patients with acute leukemia (A1 evidence level). outbreaks in the US and Asia of Fusarium keratitis in contact Itraconazole decreased the risk of the development of lens wearers [11–15]. Early in 2006, the US Centers for

THE JOURNAL OF INVASIVE FUNGAL INFECTIONS VOL 1 NO 1 2007 31 ZEINA A KANAFANI

Disease Control and Prevention (CDC) received reports of formation on contact lenses have contributed to the high several cases of Fusarium keratitis among contact lens treatment failure rates associated with these outbreaks. wearers. An investigation was launched and revealed 86 confirmed cases in 29 states [11]. The most commonly References isolated species was F solani (12 of 16; 75%). Molecular 1. Betts RF, Rotstein C, Talwar D et al. Comparison of micafungin and caspofungin for candidemia or invasive candidiasis [Abstract M-1308a]. Presented at The 46th Annual analysis revealed multiple genotypes of F solani. The Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, organism was cultured from opened contact lens solution CA, USA, September 27–30, 2006. 2. Arrieta AC, Telles-Filho F, Berezin E et al. for the Micafungin Invasive Candidiasis Study bottles and lens cases but not from unopened solution Group. A randomized, double-blind trial comparing micafungin and liposomal bottles. A case–control study was then performed to identify amphotericin B in pediatric patients with invasive candidiasis [Abstract M-1308b]. Presented at The 46th Annual Interscience Conference on Antimicrobial Agents risk factors for acquiring Fusarium keratitis [12]. Forty-four and Chemotherapy, San Francisco, CA, USA, September 27–30, 2006. 3. Raad II, Hanna H, Boktour M et al. Posaconazole compared to high-dose lipid cases were included in the analysis and were matched to formulations of amphotericin B as salvage therapy for invasive aspergillosis in patients 83 controls who were adult contact lens wearers from the with hematologic malignancy [Abstract M-874]. Presented at The 46th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, same neighborhoods as the cases. Multivariable regression CA, USA, September 27–30, 2006. showed that the use of Bausch & Lomb’s (Rochester, NY, 4. Raad II, Hanna H, Boktour M et al. The combination of caspofungin and voriconazole as primary and salvage therapy of invasive aspergillosis in hematologic malignancy patients USA) ReNu with MoistureLoc contact lens solution was [Abstract M-889]. Presented at The 46th Annual Interscience Conference on Antimicrobial associated with the highest risk for developing Fusarium Agents and Chemotherapy, San Francisco, CA, USA, September 27–30, 2006. 5. Kontoyiannis DP, Ratanatharathorn V, Van Burik J et al. Micafungin alone or in keratitis (OR 19.0, 95% CI 4.5–80.9). Other risk factors combination with other licensed antifungal therapy in bone marrow transplant recipients with invasive aspergillosis [Abstract M-878]. Presented at The 46th Annual Interscience included the reuse of old solution for contact lens storage Conference on Antimicrobial Agents and Chemotherapy, San Francisco, CA, USA, (OR 2.9, 95% CI 1.3–6.3). All of the findings detailed above September 27–30, 2006. 6. Flynn PM, Seibel N, Arrieta AC et al. Treatment of invasive aspergillosis in pediatric led the investigators to conclude that extrinsic contamination patients with micafungin alone or in combination with other systemic antifungal agents [Abstract M-891]. Presented at The 46th Annual Interscience Conference on Antimicrobial of contact lens solutions had occurred, and that the cause of Agents and Chemotherapy, San Francisco, CA, USA, September 27–30, 2006. this outbreak is multifactorial. 7. Cornely OA, Bohlius J, Ullmann AJ et al. Evidence-based assessment of antifungal prophylaxis in cancer patients: a systemic analysis of 15 277 episodes [Abstract M-879]. Another large outbreak of Fusarium keratitis occurred in Presented at The 46th Annual Interscience Conference on Antimicrobial Agents and Asia and was subject to an extensive investigation [13]. Chemotherapy, San Francisco, CA, USA, September 27–30, 2006. 8. Chandrasekar P, Winston DJ, Ullmann AJ et al. Impact of azole prophylaxis on colonization Genotyping of isolates from 61 contact lens wearers in and resistance development [Abstract M-306]. Presented at The 46th Annual Interscience Singapore suggested possible relatedness of the strains, Conference on Antimicrobial Agents and Chemotherapy, San Francisco, CA, USA, September 27–30, 2006. pointing towards a common source of infection, at least in 9. Cornely OA, Bohme A, Vehreschild J et al. Evaluating voriconazole as primary antifungal some patients. prophylaxis during induction chemotherapy for acute myelogenous leukemia [Abstract M-884]. 46th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy. Sutton et al. reported on the susceptibility of F solani San Francisco, CA, USA, September 27–30, 2006. isolates to antifungals at a reference laboratory in San 10. Rijnders BJ, Slobbe L, for the Prof Study Investigators. Aerosolized liposomal AmphoB to prevent invasive aspergillosis during prolonged neutropenia: randomized placebo- Antonio (TX, USA) [14]. The isolates were resistant to a controlled trial [Abstract M-1308c]. 46th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, CA, USA, September 27–30, 2006. number of antifungal agents, including fluconazole, 11. Grant GB, O’Donnell K, Srinivasan A et al. Fusarium Keratitis Investigation Team. caspofungin, itraconazole, posaconazole, and AmB. Slightly Epidemiology and molecular analysis of a multistate Fusarium keratitis epidemic [Abstract M-1301]. 46th Annual Interscience Conference on Antimicrobial Agents lower MICs were observed with voriconazole. Synergy and Chemotherapy, San Francisco, CA, USA, September 27–30, 2006. testing using various combinations of antifungals gave 12. Chang DC, Wannemuehler K, Lewis F et al. Risk factors for contact lens-associated Fusarium keratitis – United States [Abstract M-1302]. Presented at The 46th Annual mostly indifferent results, except in two cases where Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, enhanced activity with the combination of voriconazole plus CA, USA, September 27–30, 2006. 13. Chai L, Wang Y, Koh TH et al. Fusarium Keratitis Investigation Team. Genotyping of terbinafine was observed. The refractoriness of Fusarium Fusarium keratitis outbreak by randomly amplified polymorphic DNA (RAPD) and repetitive extragenic palindromic sequence based PCR (REP-PCR) [Abstract M-1303]. infections to antifungal therapy was reinforced by the Presented at The 46th Annual Interscience Conference on Antimicrobial Agents and findings of Imamura et al. that Fusarium spp have the ability Chemotherapy, San Francisco, CA, USA, September 27–30, 2006. 14. Sutton DA, Rinaldi M, Fothergill AW. In vitro susceptibility for Fusarium solani revisited to form biofilms on soft contact lenses [15]. in light of the current Fusarium keratitis outbreak [Abstract M-361]. Presented at Twenty-five patients (36%) in the US and five patients The 46th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, CA, USA, September 27–30, 2006. (8%) in Singapore who had Fusarium keratitis required 15. Imamura Y, Chandra J, Mukherjee PK et al. Fusarium biofilms on soft contact lenses: corneal transplantation [11,13]. It appears that the innate characterization and antifungal susceptibility [Abstract M-910a]. Presented at The 46th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy, reduced susceptibility of the organism combined with biofilm San Francisco, CA, USA, September 27–30, 2006.

32 THE JOURNAL OF INVASIVE FUNGAL INFECTIONS VOL 1 NO 1 2007 THE JOURNAL OF INVASIVE FUNGAL INFECTIONS

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