mycology - ecmm.euecmm.eu/files/ecmm_01_2008_a3.pdf · journal: mikologia lekarska (medical...

Getting things doneAfew weeks ago the ECMM has moved its domicile to Basel, Switzerland.

Many societies and organizations in Europe and beyond have done this inthe past. We are now officially a non profit organization stationed in Switzerland.Our Fellow societies in this country are among others the FIFA, UEFA and Euro-pean Society for Clinical Microbiology and Infectious Diseases. However, it remainsa pity that our Swiss medical mycology colleagues were not able yet to erect a SwissSociety for Medical Mycology. We would like to have them among the national so-cieties affiliated to the ECMM. Some of our current members countries do not havea national mycological society but are rather working groups from dermatological ormicrobiological societies. ECMM should try to stimulate and help erecting multidis-ciplinary societies for medical mycology in every European country.

At the recent ECMM Council Meeting several decisions were made regardingthe new Executive Board and the venue of the 2010 ECMM educational meetingand the 2011 TIMM meeting. After 6 years of commitment to the Confederation,Prof. Emmanuel Roilides and Prof. Martin Schaller resigned as General Secretaryand Treasurer respectively. Six years is the maximum term for participating in theExecutive Council and I would like to thank them both for their invaluable effortsand support to create the Confederation as it is now. The new executive committeewas elected after a close race. Prof. George Petrikkos will serve as the new GeneralSecretary and Prof. Cornelia Lass-Flörl as the new Treasurer. The Council gave methe green light to continue my term as President for another 3 years. The three of uswill do our utmost best to fulfill the primary goal of the Confederation, organizing

and promoting the science and all aspects of medicalmycology in Europe and if necessary world wide. Re-garding the last objective we have been promotingmedical mycology in Africa by supporting alreadythree Pan African Medical Mycology (PAMMS)meetings. The next, ECMM and ISHAM sponsored,PAMMS III will take place in February 2009 in Nige-ria and I suggest you to attend this meeting in this ex-citing continent, if possible. You can read more else-where in this newsletter. Our 2008 ECMM education-al meeting was held during the International Union ofMicrobiological Societies gathering in Istanbul earlyAugust of this year. Two ECMM working groups

Mycologynewsletter 1/2008

E C M MEuropean Confederation of Medical Mycology

C E M MConfédération Européenne de Mycologie Médicale

The ECMM/CEMM Mycology Newsletter is mailedto the members of the national societies affiliatedto the European Confederation of Medical Myco-logy (about 3000 in 24 different countries)

Contents

1 Getting things done2 ECMM Council3 Affiliated Societies4 Join the new ECMM website!

ECMM Working Groups05 ECMM Survey of Infections due to

Fusarium species in Europe08 ECMM Survey of Coccidioidomycosis

in Europe

Special report on 7th InternationalConference on Cryptococcus and Cryptococcosis

11 Opening Address11 The Immune Response13 Cell Wall and Capsule13 West Meets East15 Gene Regulation and Signaling 16 Epidemiology, Molecular Typing,

Population Genetics17 Virulence Factors18 Tissue Tropism20 Sex, Mating, and Evolution21 Clinical Sessions23 Genomics Workshop

Congress reports25 Report on 3rd Advances Against As-

pergillosis27 Report on Three ECMM Symposia at

the IUMS 2008 31 Report on 1st International Forum on

Zygomycosis32 Report on 34th Annual Meeting of the

European Group for Blood andMarrow Transplantation

Announcements34 Trends in Medical Mycology-4, Athens,

October 200935 ISHAM 2009: The 17th Congress in

Tokio36 ISHAM Working Group on

Filamentous fungi and chronicrespiratory infections in cystic fibrosis, Angers, June 2009

37 3rd Pan African Medical MycologySociety (PAMMS) Conference, Abuja,February 2009

Join the new ECMM website!http://www.ecmm.eu

(continued on page 4)

Jacques F. Meis

All-Russian National Academy of Mycology President: Y.V. Sergeev Vicepresident, Head of Medical Section: S.A. Burova Secretary: A.Y. Sergeev (ECMM delegate)Treasurer: V.M. LeschenkoMembership 2008: 246Website: www.mycology.ruAsociación Española de Micología (AEM)Sección de Micología MédicaPresident: JG. Quindós AndrésVicepresident: M.C. RubioSecretary: J. Pemán GarcíaTreasurer: F.L. Hernando EchevarríaPresident Medical Mycology Section: F. Sánchez Reus (ECMM delegate)Membership 2008: 223 National meeting: Every two years. A workshop meeting (“Forum Micológico”) isscheduled the years between National MeetingsJournal: Revista Iberoamericana de MicologíaWebsite: www.reviberoammicol.com/AEMAssociação Portuguesa de Micologia Médica(ASPOMM)President: M. RochaVicepresident: R.M. VelhoSecretary: M.L. Rosado (ECMM delegate)Treasurer: M. GardeteMembership 2008: 50Austrian Society for Medical Mycology(ASMM)/Österreichische Gesellschaft fürMedizinische Mykologie (ÖGMM)President: B. Willinger Vicepresident: C. Lass-Flörl (ECMM delegate),H.-J. Dornbusch Secretary: W. BuzinaVicesecretary: G. Ginter-HanselmayerTreasurer: C. SpethVicetreasurer: J. RainerMembership 2008: 112National meeting: twice a yearWebsite: www.oegmm.atBritish Society for Medical Mycology (BSMM)President: E. M. Johnson (ECMM delegate)General Secretary: S. HowellMeetings Secretary: G. MoranTreasurer: D.M. MacCallumMembership 2008: 302 National meeting: 28 th - 31st March 2009,London Newsletter: BSMM NewsletterWebsite: www.bsmm.orgBulgarian Mycological Society (BMS)President: T. Kantardjiev (ECMM delegate)Vicepresident: G. MateevSecretary: A. KouzmanovTreasurer: T. VelinovMembership 2008: 80National meeting: 26-29 May 2009Website: www.bam-bg.netCommittee for Medical Mycology of

Czechoslovak Society for Microbiology (CSSM)President: K. Mencl (ECMM delegate)Secretary: P. HamalTreasurer: J. GabrielMembership 2008: 16 Newsletter: Bulletin of CSSMDanish Society for MycopathologiaPresident: J. Stenderup (ECMM delegate)Vicepresident: B. AndersenSecretary: B. KnudsgaardTreasurer: J. Stenderup Membership 2006: 25National meeting: twice a yearNewsletter: Report from the Danish Society forMycopathology Deutschsprachige Mykologische Gesellschaft e.V. (DMykG)President: O. Cornely Vicepresident: M. Schaller (ECMM delegate)Secretary: P.-M. Rath Treasurer: C. HiplerMembership 2008: 478 National meeting: 3-5 September 2009, CologneJournal: MycosesNewsletter: Mykologie Forum (4 issues/year)Website: www.dmykg.de/start2.htmlFederazione Italiana di Micopatologia Umana eAnimale (FIMUA)President: S. OliveriVicepresident: A. NovelliSecretary: M. SanguinettiTreasurer: L. ValloneECMM delegate: M.A. VivianiMembership 2008: 160National meeting: Milano 2010Website: www.fimua.itFinnish Society for Medical MycologyPresident: R. VisakorpiVicepresident: T. PutusSecretary: V. RatiaTreasurer: O. LindroosECMM delegate: P. KuuselaMembership 2008: 88 National meeting: February 11, 2009Newsletter: Sienet ia Terveys (Fungi and Health)Hellenic Society of Medical Mycology President: G. Samonis Vicepresident: G.L. Petrikkos (ECMM delegate)Secretary: A.M. ZiouvaTreasurer: H. Papadogeorgaki Membership 2008: 81Website: www.hsmm.grHungarian Dermatological SocietyMycology SectionPresident: G. Simon (ECMM delegate)Secretary: N. ErősMembership 2008: 61Israel Society for Medical MycologyPresident: E. SegalVicepresident: I. PolacekSecretary: I. Berdicevsky (ECMM delegate)

Treasurer: D. EladMembership 2008: 50 National meeting: twice a yearMycology Group of Bosnia HercegovinaPresident: L. Ozegovic (ECMM delegate)Secretary: M. BabicMembership 2005: 19National meeting: twice a yearNetherland Society for Medical Mycology(NVMy)President: J.F.G.M. Meis (ECMM delegate)Secretary: E.P.F. YzermanTreasurer: M.H. DammerScientific Secretary: G. S. de HoogMembership 2008: 119 Newsletter: NVMy NewsletterWebsite: www.nvmy.nlNordic Society for Medical Mycology (NSMM)President: M.C. Arendrup (ECMM delegate)Vicepresident: Lena KlingsporSecretary: P. Gaustad Treasurer: D.M.L. SaunteMembership 2008: 214Newsletter: at web siteWebsite: www.nsmm.nuPolish Dermatologic Society-Mycology SectionPresident: E. BaranVicepresident: Z. Adamski, R. MaleszkaSecretary: R. Bialynicki-Birula (ECMM delegate)Treasurer: A. Hryncewicz-GwozdzMembership 2008: 100National meeting: Krakow 2012Journal: Mikologia Lekarska (MedicalMycology)Romanian Society of Medical Mycology andMycotoxicology (RSMMM)President: M. Mares (ECMM delegate)Vicepresident: B. DorofteiSecretary: A. StefanacheTreasurer: L. MalicMembership 2008: 80National meeting: National Meeting every twoyears and Congress every four yearsJournal: Fungi & MycotoxinsBooks: Syntheses of Medical Mycology (for Continuing Medical Education)Website: www.fungi.ro / www.journal.fungi.roSociété Belge de Mycologie Humaine etAnimale/Belgische Vereniging Voor Menselijkeen Dierlijke MycologiePresident: I. SurmontVicepresident: K. Lagrou (ECMM delegate), F. SymoensSecretary: M. Van EsbroeckTreasurer: P. HuynenScientific Secretary: E. De LaereMembership 2008: 181Website: www.medmycol.beSociété Française de Mycologie MédicalePresident: B. Dupont (ECMM delegate)Vicepresident: N. Contet-Audonneau, R. Grillot, C. GuiguenSecretary: P. RouxTreasurer: A. DatryMembership 2008: 350National meeting: June 17-19, 2009, PoitiersJournal: Journal de Mycologie MédicaleWebsite: http://pagesperso-orange.fr/sfmmSwedish Society for Clinical MycologyPresident: J. FaergemannVicepresident: T. KaamanSecretary: L. Klingspor (ECMM delegate)Treasurer: M.L. von Rosen Membership 2008: 80Turkish Microbiological SocietyMycology SectionPresident: Ö. AngSecretary: A. AgaçfidanTreasury: D. YaylaliECMM delegate: S. ArikanMembership 2008: 150Newsletter: Bulletin of the TurkishMicrobiological Society

Mycology newsletter - December 2008 Mycology newsletter - December 2008

Prof. Martin Schaller Eberhard-Karls-UniversitätUniversitäts-HautklinikLiebermeisterstrasse 25D-72070 Tübingen, GermanyTel +49 7071 2984555 - Fax +49 7071 295113E-mail: [email protected]

Dr. Gyula SimonMikroMikoMed LtdEndrődi St 60/B

32

ECMM/CEMMMycology Newsletter

Editorial Advisory BoardJacques F. Meis Malcolm RichardsonEmmanuel RoilidesMartin SchallerMaria Anna Viviani (Editor)

Editorial officec/o Dipartimento di Sanità Pubblica,Microbiologia, VirologiaSezione di Sanità PubblicaUniversità degli Studi di MilanoVia Pascal 36, 20133 Milano, Italy

Direttore responsabileIvan Dragoni

Art Director Luigi Naro

Contributions from: Anne Beauvais, Tihana Bicanic, Teun Boekhout, Jean-Philippe Bouchara,Jenny Bryan, Sybren de Hoog,Maurizio Del Poeta, Bertrand Dupont, Ifeoma Enweani, Mahmoud Ghannoum, Angie Gelli, Cornelia Lass-Flörl, Jean-Paul Latgé, Stuart M. Levitz,Jenny K. Lodge, Jacques F. Meis, Kirsten Nielsen, Hideoki Ogawa, Michal Olszewski, Peter G. Pappas, George Petrikkos, Malcolm Richardson, Emmanuel Roilides, Alexey Sergeev, Tania C. Sorrell, Anna Maria Tortorano, Maria Anna Viviani

© Copyright 2008 by European Confederation of MedicalMycology

Official Office:c/o Steiger, Zumstein & Partners AGNauenstrasse 494052 Basel, Switzerland

Registrazione Tribunale di Milano n. 749 del 25.11.1997

ECMM CouncilDr. Jacques F.G.M. Meis (President)Dept. of Medical Microbiology and Infectious Diseases Canisius-Wilhelmina Hospital Weg door Jonkerbos 100P.O. Box 9015NL-6500 GS Nijmegen, The NetherlandsTel +31 24 365 7514 - Fax +31 24 365 7516E-mail: [email protected]. Georgios L. Petrikkos (General Secretary)National and Kapodistrian University of Athens Laiko General Hospital 75, M. Asias Street GR-115 27, Athens, GreeceTel +30210 7462636Fax +30210 7462635E-mail: [email protected]; [email protected]. Cornelia Lass-Flörl (Treasurer)Department für Hygiene, Mikrobiologie undSozialmedizin, Sektion Hygiene undmedizinische Mikrobiologie, Medizinische Universität InnsbruckFritz Pregl Str. 3/III6020 Innsbruck, AustriaTel +43 512 9003 70725Fax +43 512 9003 73700E-mail: [email protected]. Maria Anna Viviani (Mycology Newsletter Editor)Laboratorio di Micologia MedicaDipartimento di Sanità Pubblica, Microbiologia, VirologiaSezione di Sanità PubblicaUniversità degli Studi di MilanoVia Pascal 36I-20133 Milano, ItalyTel +39 02 503 151 44 / 45Fax +39 02 503 151 46E-mail: [email protected]. Alexey Y. Sergeev (Website Editor)Malaya Bronnaya str. 20 b. 1.Moscow 103104, RussiaTel +7 095 5046506Fax +7 095 2592165E-mail: [email protected] Dr. Maiken Cavling ArendrupUnit of Mycology and Parasitology - ABMPStatens Serum Institut, building 43/214CDK-2300 Copenhagen, DenmarkTel +45 32 68 32 23 - Fax +45 32 68 81 80E-mail: [email protected]. Sevtap ArikanHacettepe University Medical SchoolDepartment of Microbiology and ClinicalMicrobiology06100 Ankara, TurkeyTel +90 312 3051562Fax +90 312 3115250E-mail: [email protected]. Israela Berdicevsky Department of MicrobiologyThe Bruce Rappaport Faculty of MedicineP.O. Box 9649Haifa 31096, IsraelTel +972 4 829 5293 - Fax +972 4 829 5225E-mail: [email protected]. Rafal Bialynicki-BirulaDepartment of Dermatology Wroclaw Medical UniversityChalubinskiego Str. 1PL-50-368 Wroclaw, PolandMobile: +48 601990167E-mail: [email protected]

Prof. Bertrand Dupont Hôpital NeckerMaladies infectieuses et tropicales149 rue de SèvresF-75015 Paris, FranceTel +33 1 4438 1742 - Fax +33 1 4219 2732E-mail: [email protected]. Elizabeth M. Johnson HPA Mycology Reference LaboratoryHPA South West LaboratoryMyrtle Road, KingsdownUK-Bristol BS2 8EL, United KingdomE-mail: [email protected]. Todor Kantardjiev National Center for Infectious Diseases Laboratory of Mycology26, Yanko Sakazov Blvd. BG-1504 Sofia, BulgariaTel +359 2 8465520 - Fax +359 2 9433075E-mail: [email protected]: [email protected]. Lena Klingspor Dept. of Clinical Bacteriology, F72Karolinska University Laboratory, HuddingeKarolinska University Hospital S-141 86 Huddinge, Sweden Tel +46 8 5858 7839/Beeper 3621Fax +46 8 5858 1125E-mail: [email protected]. Pentti KuuselaDivison of Clinical Microbiology/HUSLABHelsinki University Central HospitalPO Box 400 (Haartmaninkatu 3)FIN-00029 Hus, FinlandE-mail: [email protected]. Katrien LagrouDienst laboratoriumgeneeskundeUZ LeuvenHerestraat 49 B-3000 Leuven, BelgiumTel +32 16 347098E-mail: [email protected]. Mihai MaresOP 6, CP 1356, Iasi, RomaniaTel +40232 407 316 / +40722 465 789Fax +40232 407 316E-mail: [email protected]. Karel MenclPardubice Regional Hospital, Inc.Laboratory of Medical MycologyKyjevská 44532 03 Pardubice, Czech RepublicTel +420 466 013 202 - Fax +420 466 013 202E-mail: [email protected]. Ladislav OzegovicANUBIH - Bistrik 771000 Sarajevo, Bosna i HercegovinaTel +387 33 206034 - Fax +387 33 206033E-mail: [email protected]. Ferrán Sánchez Reus Servicio de MicrobiologíaHospital de la Santa Creu i Sant PauC/Sant Antoni Maria Claret, 167E-08025 Barcelona, SpainTel: +34 932 919 069 - Fax: +34 932 919 070E-mail: [email protected]. Laura Rosado Institute of HealthAv. Padre Cruz1649-016 Lisboa Codex, PortugalTel +351 217.519.247 - Fax +351 217.526.400E-mail: [email protected]

ECMM Affiliated Societies(Information provided by the member Societies)

H-1026-Budapest, HungaryTel +36 1 2990042Fax +36 1 2990043E-mail: [email protected]. Jørgen StenderupDanish Society for Mycopathology17A Hjortholms AlleDK-2400 København NV, Denmark Tel +45 3860 7879Fax +45 9927 2666E-mail: [email protected]

Fusarium species cause a variety of infec-tions in humans, including superficial, local-ly invasive, and disseminated infections. Theclinical presentation largely depends on theimmune status of the host and the fungalportal of entry.(1) Superficial infections,such as keratitis and onychomycosis, areusually observed in immunocompetent indi-viduals, whereas invasive and disseminatedinfections occur in immunocompromised pa-tients and are mainly associated with pro-longed and profound neutropenia or severeT-cell immunodeficiency.(2)

Among the more than 50 Fusariumspecies identified, twelve have been de-scribed as causes of human infection. F. solani is the most frequently reportedFusarium species and is the cause of approx-imately 50% of the Fusarium infections; thenext most prevalent species, in order, are F. oxysporum (20%), F. verticilloides (10%),and F. moniliforme (now classified as F. ver-ticilloides, 10%).(1,3) In contrast with datafrom the literature, in Italy F. verticilloidesresulted the most prevalent species (41%)followed by F. solani (25%). In particular, F. verticilloides was the most frequentspecies (57%) in deep-seated infections andF. solani is more common in superficial in-fections (46%).(4)

Fusarium species are relatively resistantto most antifungal agents. Careful analysis,however, shows that different species havedifferent patterns of susceptibility.(1) The

majority of F. solani isolates exhibited re-duced susceptibility to azoles.(1,4-8)

The prognosis of fusariosis in immuno-compromised host is poor and also the treat-ment of skin and nail infections is frustratingand failure of systemic and local treatment iscommon.

The main purpose of this study is to un-derstand the epidemiology of fusariosis inEurope, collecting information on the pa-tients infected by Fusarium (risk factors, lo-calization/extent of infection, diagnosis, anti-fungal treatment and outcome) and on theinfecting isolates (identification by molecu-lar methods, in vitro susceptibility to anti-fungal agents).

Study designCases of fusariosis, deep seated as well as

superficial infections, for which the infectingisolate is available, will be recorded on aquestionnaire and the isolate collected andcharacterized. The form and the correspond-ing isolates will be collected in the nationalcoordinator laboratory and strains studied.

The prospective study is planned to starton January 1st, 2009 and it will last for twoyears. Two years (2007 and 2008) retrospec-tive data will be also collected.

Investigators interested in participatingto this study as national coordinator for theircountry are welcome.

Anna Maria Tortorano

Working Groups

5Mycology newsletter - December 20084 Mycology newsletter - December 2008

convened a symposium on Candidosis inthe Intensive Care (Chair: LenaKlingspor) and Zygomycosis (Chair:George Petrikkos). Recruitment of pa-tients in the latter study was closed ear-lier this year after 3 years. Given thehighly successful outcome of thisECMM working group on Zygomyco-sis, headed by Prof. Petrikkos, we haveliaised with ISHAM to start a new jointECMM/ISHAM working group on Zy-gomycosis covering Europe, North- andSouth America, the Indian subcontinentand if possible Africa. This project is tru-ly in line with the ECMM objectives setforth in our Charter. Previous ECMMworking groups were on candidemia,cryptococcosis, histoplasmosis, nocar-diosis, scedosporiosis, black yeasts andtinea capitis. All studies were successful-ly concluded with one or more publica-tions on behalf of the ECMM. To thosemembers who walk around with goodideas, it is always possible to come upwith initiatives for new working groups.The latest initiatives from ECMM mem-bers are future working groups on fusar-iosis and coccidioidomycosis in Europe.

The 2010 ECMM educational meet-ing will be together with our fellow Ital-ian medical mycologists and TIMM-5will take place in the autumn of 2011 inValencia, Spain. For all of you it is nowtime to think ahead of TIMM-6 in 2013and the educational ECMM meeting in2012. This might be a change for yournational society to host the largest med-ical mycology meeting in the world.

The digital focus of our society,www.ecmm.eu, has undergone a majorreconstruction. The ECMM Websitecommittee under the direction of Prof.Alexey Sergeev has prepared a new dig-ital communication board for theECMM members. I hope you will visitthe website regularly to browse andgather information.

The year 2008 runs to an end. I wishthat you were able to achieve all yourpersonal goals set for this year and areprepared for the changes that will takeplace in the new year. ECMM will fly in-to a new exciting new year of changeand things to look forward to in 2009.

Jacques F. MeisECMM President

Getting things done(continued from page 1) Join the new ECMM website!

The new version of ECMM website is ready at http://www.ecmm.eu.Under the recommendations of ECMM website committee (M.C. Arendrup, S.

Arikan, J. Brandão, J. Meis, E. Roilides, A.Y. Sergeev, M.A. Viviani), it was de-cided to maintain the initial site design proposed by Prof F.C. Odds, but to extendits functionality. To do so, we have installed the famous European open-sourceframework, Drupal.

The four major parts of the website are dedicated to Confederation itself,ECMM events, projects and Newsletter. The “About ECMM” page tracks ECMMpast and describes its current state, holding important documents and historical im-ages. The “Events” page keeps records of all meetings and conferences held byConfederation since 1993. The “Working groups” page lists all completed surveysand follows active working groups. It will be further extended to allow membersjoining working groups online. The “Newsletter” page provides information onECMM Mycology Newsletter and allows users to download all of its issues.

The new website will update you on all important events in Medical Mycology,new publications, research projects and meetings. In development stage is citationtracker that aggregates the latest publications from medical mycology journals.Events calendar is planned to provide the announcements of all mycological meet-ings and courses.

What extras does the new ECMM website offer? First of all, now it is really in-teractive. Everyone may register and use the site. Registered ECMM members cancontact each other, keep in touch with researchers from other countries, subscribefor events and join projects. Now you can comment on each event or publication,vote in online polls, use forums. ECMM mem-bers and National Societies can start their ownblog and share their news and other informationwith colleagues.

Your opinion is important. As the registeredmember online, you may comment on almost anypage of the website. Propose your ideas of web-site development, ask for new features and im-provements. We are waiting for your input.

Join the new ECMM online community! Reg-ister at http://www.ecmm.eu

Alexey SergeevWebsite Editor

ECMM Survey of Infections due toFusarium species in Europe

Appointed nationalCountry coordinator Institution Address Fax/Tel Email

Austria Cornelia Lass-Flörl Dept. Hygiene, Social Medicine and Microbioloy Fritz Pregl Str. 3/III +43 512 9003 73700Innsbruck Medical University Innsbruck, Austria +43 512 9003 70725 [email protected]

Czech Petr Hamal Institute of Microbiology Hnevotinska 3 +420-58-563-2417 [email protected] Palacky University, Faculty of Medicin CZ-775 15 Olomouc, Czech Republic +420-58-563-2403 [email protected]

Denmark Maiken Cavling Arendrup Unit of Mycology and Parasitology Statens Serum Institut, building 43/214C +45 32 68 81 80Dept. Bacteriology, Mycology and Parasitology DK-2300 Copenhagen, Denmark +45 32 68 32 23 [email protected]

Germany Markus Ruhnke Medizinische Klinik und Poliklinik II, Charité Charitéplatz 1 +49 30450 513907Campus Mitte der Humboldt - Universität zu Berlin 10117 Berlin, Germany +49 30450 513036 [email protected]

Greece Olga Paiara Clinical Microbiology 45-47Hipsilandou street Department Evangelismos General Hospital 10676 Athens, Greece +30 2107217704 [email protected]

Ireland Tom Rogers Clinical Microbiology St James's Hospital +35 31 8968566Trinity College Dublin Dublin 8, Ireland +35 31 8962131 [email protected]

Italy Anna Maria Tortorano Mycology Laboratory Convenor Dept. Public Health-Microbiology-Virology Via Pascal 36 +39 02 503 15146

University of Milan 20133 Milano, Italy +39 02 503 15145 [email protected]

Spain Ferran Sanchez Microbiología C/Sant Anton Maria Còaret 167Hospital de la Santa Creu i San Pauli 08025 Barcelona, Spain +34 932 919 069 [email protected]

Sweeden Lena Klingspor Division of Clinical Bacteriology, F72 Karolinska University Laboratory, HuddingeKarolinska University Hospital + 46 8 5858 1125 [email protected] SE-141 86 Stockholm +46 8 5858 7839 [email protected]

Turkey Sevtap Arikan Mycology Laboratory Hacettepe University Medical SchoolDept. Microbiology and Clinical Microbiology 06100 Ankara, Turkey Fax +90 312 3115250 [email protected]

REFERENCES1. Nucci M, Anaissie E. 2007. Fusarium in-

fections in immunocompromised pa-tients. Clin. Microbiol. Rev. 20:695-704.

2. Nucci M, Anaissie E. 2002. Cutaneousinfection by Fusarium species in healthyand immunocompromised hosts: impli-cations for diagnosis and management.Clin. Infect. Dis. 35:909-920.

3. Seifert KA, Aoki T, Baayen RP, et al.2003. The name Fusarium moniliformeshould no longer be used. Mycol. Res.107: 643-644.

4. Tortorano AM, Prigitano A, Dho G, Es-posto MC, Gianni C, Grancini A, OssiC, Viviani MA. 2008. Species distribu-tion and in vitro antifungal susceptibilitypatterns of 75 clinical isolates of Fusari-um from Northern Italy. Antimicrob.Agents Chemother. 52:2683-2685

5. Arikan S, Lozano-Chiu M, Paetznick V, Nangia S, Rex JH. 1999. Microdilu-tion susceptibility testing of ampho-tericin B, itraconazole, and voriconazoleagainst clinical isolates of Aspergillusand Fusarium species. J. Clin. Microbiol.37:3946-3951.

6. Azor M, Gené J, Cano J, Guardo J.2007. Universal in vitro antifungal resis-tance of genetic clades of the Fusariumsolani species complex. Antimicrob.Agents Chemother. 51:1500-1503.

7. Paphitou NI, Ostrosky-Zeichner L, Paet-znick VL, Rodriguez JR, Chen E, RexJH. 2002. In vitro activities of investiga-tional triazoles against Fusarium species:effects of inoculum size and incubationtime on broth microdilution susceptibili-ty test results. Antimicrob. AgentsChemother. 46:3298-3300.

8. Alastruey-Izquierdo A, Cuenca-EstrellaM, Monzon A, Mellado E, Rodriguez-Tudela JL. 2008. Antifungal susceptibili-ty profile of clinical Fusarium spp. iso-lates identified by molecular methods. J. Antimicrob. Chemother. 61:805-809.

Working Groups Working Groups

6 7Mycology newsletter - December 2008 Mycology newsletter - December 2008

ECMM survey: Fusarium Infections in EuropeEpidemiological and clinical form

Country: National Coordinator:

Centre: City:

OUTCOME OF FUSARIUM INFECTION| |Cure, date | |Death, date | |Lost, date | |Relapse, date

Last culture/s positive for Fusarium (specify sample and date)

PATIENTPatient code: Sex: | |M | |F Birthdate (mm/yyyy) | | | / | | | | | Country of birth: Country of residence: Occupation:

Ward of hospitalization: | |Hematology | |ICU | |Other, specify

FUSARIUM PATHOLOGYDate of diagnosis (dd/mm/yy) | | | / | | | / | | | | |Disseminated infection | |Localized infection | |Colonization

Involved site/s:

| |blood | |lung | |pleura | |peritoneum | |cornea | |skin | |nails | |other, specify

Detailed data (clinical manifestations, localization, imaging …….)

UNDERLYING DISEASE/FACTORS| |Autoimmune disease, specify date of diagnosis | | | / | | | / | | || |Leukemia / | |Lymphoma, specify date of diagnosis | | | / | | | / | | || |Solid cancer, specify date of diagnosis | | | / | | | / | | || |Hemopoietic stem cell transplant of diagnosis date | | | / | | | / | | |

| |autologous | |allogeneic: | |matched related; | |matched unrelated; | |mismatched; | |aplotype; | |umbelical cord

| |myeloablative: | |related; | |unrelate | |non myeloablative: | |related; | |unrelated

| |Bone marrow transplantt of diagnosis date | | | / | | | / | | || |Graft versus host disease: | |acute; | |chronic date of diagnosis | | | / | | | / | | || |Severe neutropenia (<500/mm3), specify time and duration of neutropenia

| |Immunosuppressive drugs, specify drugs, dosage, period of treatment

| |Corticosteroids, specify drugs, dosage, period of treatment

| |Chronic obstructive pulmonary disease, specify grade

| |Surgery, specify of diagnosis date | | | / | | | / | | || |Solid organ tranplant, specify of diagnosis date | | | / | | | / | | || |Diabetes: | |type I; | |type II date of diagnosis | | | / | | | / | | || |AIDS CD4 number/mm3: date of diagnosis | | | / | | | / | | || |Accidental trauma, specify of diagnosis date | | | / | | | / | | || |Dialysis: | |hemo; | |peritoneal

| |Stay in ICU APACHE II score: SAPS III score: period of stay:

| |Use of contact lens, specify type Contact lens solution used:

| |Other, specify

TREATMENT OF FUSARIUM INFECTIONAntifungal therapy Patient weight:

Drug 1: daily dose: from (dd/mm/yy) | | | / | | | / | | | to (dd/mm/yy) | | | / | | | / | | |Drug 2: daily dose: from (dd/mm/yy) | | | / | | | / | | | to (dd/mm/yy) | | | / | | | / | | |Drug 3: daily dose: from (dd/mm/yy) | | | / | | | / | | | to (dd/mm/yy) | | | / | | | / | | |

Surgery, specify of diagnosis date | | | / | | | / | | |

MYCOLOGYDirect microscopy and culture

Direct microscopy CultureBlood | |not done | |done | |neg. | |pos.* | |not done | |done, specify system

| |neg. | |pos. date | | | / | | | / | | |

Bronchial secr. | |not done | |done | |neg. | |pos.* | |not done | |done | |neg. | |pos. date | | | / | | | / | | |

Oral secretions | |not done | |done | |neg. | |pos.* | |not done | |done | |neg. | |pos. date | | | / | | | / | | |

Nasal secretions | |not done | |done | |neg. | |pos.* | |not done | |done | |neg. | |pos. date | | | / | | | / | | |

Pleural fluid | |not done | |done | |neg. | |pos.* | |not done | |done | |neg. | |pos. date | | | / | | | / | | |

Peritoneal fluid, | |not done | |done | |neg. | |pos.* | |not done | |done | |neg. | |pos. date | | | / | | | / | | |specify if dialytic

Biopsy, specify | |not done | |done | |neg. | |pos.* | |not done | |done | |neg. | |pos. date | | | / | | | / | | |

Skin, specify site | |not done | |done | |neg. | |pos.* | |not done | |done | |neg. | |pos. date | | | / | | | / | | |

Corneal scraping, | |not done | |done | |neg. | |pos.* | |not done | |done | |neg. | |pos. date | | | / | | | / | | |specify

Nails, specify | |not done | |done | |neg. | |pos.* | |not done | |done | |neg. | |pos. date | | | / | | | / | | |

Other, specify | |not done | |done | |neg. | |pos.* | |not done | |done | |neg. | |pos. date | | | / | | | / | | |

* presence of hyphae

HistopathologyBiopsy, specify sample/s and date | |not done | |done | |neg. | |pos.*

Autopsy, specify date | |not done | |done | |neg. | |pos.*

* presence of hyphae

Note

FUSARIUM ISOLATES SENT TO THE NATIONAL/EUROPEAN COORDINATORRef.number: Identification: Cultured from: date | | | / | | | / | | |Ref.number: Identification: Cultured from: date | | | / | | | / | | |Ref.number: Identification: Cultured from: date | | | / | | | / | | |

CORRESPONDING PHYSICIAN/MYCOLOGISTName of physician Phone Email

Name of mycologist Phone Email

9Mycology newsletter - December 2008

Background Coccidioidomycosis is a disease endemic

to parts of South-West USA (Arizona, Cali-fornia, Utah, New Mexico), Central andSouth America, caused by the dimorphicfungi Coccidioides immitis and C. posadasii,desert soil-dwelling ascomycetes. These fun-gi grow as a filamentous saprobe in the soiland as endosporulating spherules within thehost. Inhalation of arthroconidia results in asymptomatic respiratory tract disease, usual-ly mild and self-limited, in up to 40% of in-fected patients. But the disease can lastmonths and in 1% of cases disseminates be-yond the lung. CNS, lymph nodes, bone tis-sue and skin are primarily involved. Dissem-inated infections can be fatal or require life-long therapy.

Coccidioidomycosis in EuropeWhile not endemic in Europe, cases of

coccidioidomycosis occur in individuals whohave lived or travelled in endemic areas. Re-activation of infections from several years pre-vious may result from a failing immune sys-tem, as for example occurs in some AIDS pa-tients. Information of the general prevalenceof this mycosis in Europe is not available.

Because the international tourism andthe immigration from endemic countries areincreasing, physicians in Europe need to be-come more familiar with the manifestationsand with the approach to diagnosis. Travelhistory should always be sought in the eval-uation of patients. Since few fungal elementscan be present in biopsy, histology with spe-cial stains and the more sensitive culture ex-amination should always be performed. Inaddition, to avoid risk of accidental expo-sure, laboratory workers should be informedof the clinical suspicion.

Objective of the surveyThe objective of this survey is to discov-

er the prevalence of coccidioidomycosis inEurope, where and how the infection was ac-quired, the group at risk, the fungal speciesresponsible and the method by which the in-fection was diagnosed. The antifungal thera-py and the outcome will also be analysed.This will lead to a better understanding ofthis imported mycosis and will enable a co-ordinated effort to target at risk populationsand to standardize methods for the diagnosisand treatment of the disease.

Investigators interested in participatingto the study as “national coordinator” fortheir country are requested to contact Prof.B. Dupont

Study period Notification of new cases will start on the

1st January 2009. Retrospective cases since1983 will also be collected

Collection of data and isolates Notification of cases should be made us-

ing the epidemiological form for coccid-ioidomycosis reported at page 9. Data fromthe retrospective study should be compiledas soon as possible and send to the nationalcoordinator. For the prospective study theinformation should be sent as the cases arise.The isolate, if available, should be stored inthe laboratory where it was identified.Please contact your national coordinator toknow if molecular identification of species isavailable before sending the isolates accord-ing to safety national rules. Postal regula-tions on the safe packaging of these danger-ous pathogens need to be strictly followed.

Bertrand Dupont

Further information can be obtained fromProf. Bertrand Dupont([email protected]).

Working Groups

8

Convenor Prof. Bertrand Dupont Hôpital Necker, Maladies Infectieuses et Tropicales149 rue de Sèvres, 75015 Paris, FranceTel: 33 (0)1 44 38 17 42 Fax: 33 (0)1 42 19 27 32 [email protected]

Risk for European Laboratory Workers Biosafety Classification Directives recognizesthese thermally dimorphic fungi as HazardGroup 3 pathogens. The risk of laboratoryworkers is a serious one, owing to the largenumber of spores many isolates produce inculture. Serious infections have occurred inlaboratories without proper contaminant facil-ities. Clinicians should inform laboratories ifclinical material from a patient with a suspect-ed imported fungal infection is submitted formicrobiological or histopathological investiga-tion.

ECMM Survey of Coccidioidomycosis in Europe

Mycology newsletter - December 2008

Working Groups

ContaminationDate: (mm/yyyy) | | | / | | | | |Country/state: area/county: town: Mode of contamination specify:

Time (days, months or years) between contamination and first symptoms: and treatment:

DiseaseDate of diagnosis: | | | / | | | / | | |Primary infection: | | Disseminated infection: | | Relapse: | |Asymptomatic infection: | | Symptomatic: | | specify: Localisations: lung: | | infiltrate: | | nodule: | | cavity: | | lymphnode: | |

CSF: | | HTIC: | | vasculitis: | |skin: | | ulceration: | | nodule: | |

joint/bone: | | specify:

other: | | specify:

Diagnosis proceduresbiopsy: no: | | yes: | | site specify:

presence of spherules: no: | | yes: | | site specify:

positive culture: no: | | yes: | | site specify:

spp identification: immitis: | | posadasii: | | not available: | |positive serology: no: | | yes: | | not done: | |

body fluid tested specify test(s) used specify

Other (antigen, skin test) specify

ECMM survey: Coccidioidomycosis in Europe Epidemiological and clinical form

Underlying disease / Risk factors None | |

Immunosuppression | | HIV: | | CD4 cells specify: corticosteroids: | | anti-TNF: | |Solid organ transplant: | | specify:

Risk factors | | BPCO: | | pregnancy: | | diabetes: | |Other: | | specify:

CenterCountry: City: Hospital:Physician’s name:Microbiologist/mycologist’s name: email:

Patient informationNationality: Country: City: Birthdate (mm/yyyy) | | | / | | | | | Sex: | |M | |F Weight: Ethnicity: Occupation:

TreatmentSystemic antifungal: No: | | Yes: | |Drugs Route - Dosage/d Date started Date stopped comment

intrathecal antifungal: No: | | Yes: | | CSF shunt: No: | | Yes: | |Other treatment specify

OutcomeCure: No: | | Yes: | | follow up: | | | / | | | / | | | specify Improvement: No: | | Yes: | |Failure: | | Death: | | cause of death specify

Progressive chronic infection specify

Was this case published: No: | | Yes: | | Please provide reference of publication: or email a PDF copy

Other remarks:

Please email this form to your country coordinator

11Mycology newsletter - December 200810 Mycology newsletter - December 2008

Dr. Shigeru Kohno, the Con-ference Chair and Dean,

Nagasaki University School ofMedicine, warmly welcomed theconference participants to Nagasa-ki and noted that this was the firsttime the ICCC was being held inFar East Asia. He then introducedJohn Perfect, who gave the Open-ing Address. Dr. Perfect cited thelatest Center for Disease Control(USA) estimates that there areover 1,000,000 cases of cryptococ-cosis per year and, of those cases,approximately two thirds will die.He then went on to focus on whyCryptococcus is a “brainy” yeast –in other words, why it is neurotrop-ic. Dr. Perfect and his laboratoryhave examined what the require-ments are for C. neoformans to sur-vive in the cerebrospinal fluid(CSF) with the hypothesis that cer-tain gene products promote dis-semination and survival in thebrain. Of 1700 mutants that weretested, 19 could not grow in CSF.The nature of these mutations wasbeing studied.

Dr. Perfect then informed theaudience that the IDSA PracticeGuidelines for the treatment ofcryptococcosis were in the finalstages of revision and should be

published soon. He emphasizedthat amphotericin B plus 5-flucyto-sine remains the optimal choice forinduction therapy of cryptococcalmeningitis. Fluconazole is not asgood, but if practical considera-tions dictate its use, it should beused at doses >800 mg/day. In pa-tients found to be co-infected withHIV and C. neoformans, it remainsuncertain when is the best time tostart antiretroviral therapy. Onemust balance the risk of furthercomplications of AIDS with therisk of an immune response inflam-matory syndrome to the fungus. Fi-nally, Dr. Perfect addressed the is-sue of management of elevated in-tracranial pressure with the opin-ion that those with pressure about25 cm should have measures takento relieve the elevated pressure, in-cluding repeated lumbar puncturesand, if necessary, shunting.

Stuart Levitz

The Immune Response I ses-sion began with a presenta-

tion by Thomas Kozel (Universityof Nevada School of Medicine,Reno, Usa) on the interaction ofantibody and complement proteinswith the cryptococcal capsule. Dr.Kozel emphasized that the capsulegets densest as it gets closer to thecell wall. There are differences invitro versus inside the mouse as thecapsule gets denser and has moreO-acetylation when the fungus is invivo. In addition, there areserotype-specific differences in theexpression of O-acetylation groupsin the fungus’ buds. Next, Christo-pher Mody (University of Calgary,Canada) presented the results ofhis research on the mechanisms bywhich NK cells inhibit and kill C. neoformans. He emphasized

Special report

7th InternationalConference on Cryptococcusand Cryptococcosis 11-14th September, 2008, Nagasaki, Japan

From their humble beginnings of discovery as a humanpathogen in the 1890s, Cryptococcus neoformans andCryptococcus gattii have exploded onto clinical practicein this millenium. For instance a recent outbreak of C. gattii infections from Vancouver Island to NorthwestUSA has demonstrated the ability of this encapsulatedyeast to change its pathobiology and ecology. Evenmore impressive is that the CDC now estimates theglobal burden of HIV-associated cryptococcosis at 1million cases per year with estimated deaths of 680,000per year. When placed in number of estimated deathsfrom infectious diseases in Sub Saharan Africaexcluding directly AIDS only malaria and diarrhealillnesses rank higher.John R. Perfect

Special report on...

byTihana BicanicTeun Boekhout

Maurizio Del PoetaAngie Gelli

Stuart M. LevitzJenny K. LodgeKirsten Nielsen

Michal OlszewskiPeter G. PappasTania C. Sorrell

Opening Address

Nagasaki, Japan11-14 September 2008

The Immune Response

Shigeru Kohno

John Perfect

Stuart Levitz and Thomas Kozel

7th ICCC

Special report Special report

some to be the infectious propag-ule, Dr. Botts characterized theirsurface composition. He found evi-dence for a thin layer of GXM aswell as partially exposed beta-glu-cans and mannans. The session con-cluded with a presentation fromKaren Wozniak (University ofMassachusetts Medical School,Worcester, USA) examining intra-cellular events following phagocy-tosis of C. neoformans by dendriticcells. C. neoformans traffics to com-partments containing endosomesand lysosomes. Moreover, crudelysosomal extracts from dendriticcells potently killed the fungus in adose-dependent manner.

Stuart Levitz


that perforin is required. While NKcells degranulation and lose per-forin when exposed to C. neofor-mans, the NK cells subsequently“re-arm” with more perforin.

Anna Vecchiarelli (Universityof Perugia, Italy) then reviewed theimmunosuppressive effects of themajor capsular polysaccharide ofC. neoformans, GXM. She thenasked the question whether GXMcould be used to treat autoimmunediseases. Beneficial effects wereseen in an experimental model ofcollagen-induced arthritis.

The session concluded withtwo presentations selected fromthe submitted abstracts. First,Mark Krockenberger (Universityof Sydney, Australia) presenteddata on a new rat model of C. gat-tii pulmonary infection and con-trasted it to what is known aboutrat models of C. neoformans. Fi-nally, Simon Johnston (Universi-ty of Birmingham, UK) presentedintriguing data that Cryptococcuscan escape from macrophageswithout killing the host cell by aprocess termed reverse phagocy-tosis or vomocytosis.

Kazuyoshi Kawakami (TohokuUniversity Graduate School ofMedicine, Japan) opened the Im-mune Response II session by ex-amining selected aspects of the in-nate immune response to C. neo-formans. He presented data thatthe beta-glucan receptor, dectin-1,was dispensable for immunity toC. neoformans. Then, he reviewedstudies that established a criticalrole for the adapter protein,

MyD88, in host defenses againstcryptococcosis. As TLR9 utilizesMyD88 to signal, Dr. Kawakamiexamined whether TLR9 sensesDNA from C. neoformans. Hefound cytokine production follow-ing stimulation of dendritic cellswith C. neoformans DNA. Next,Stuart Levitz (University of Massa-chusetts Medical School, Worces-ter, USA) discussed immune re-sponses to mannoproteins. Theseimmunodominant proteins areheavily mannosylated via both N-linkages and O-linkages. Dr. Levitzpresented data showing thatmannoproteins are poor stimula-tors of cytokine production by den-dritic cells. However, combiningmannoproteins with TLR ligandssynergistically boosted cytokineproduction. Dr. Levitz speculated

that this combination could make agood vaccine.

Type I interferons are knownto play a critical role in viral infec-tions, but their contribution tohost defenses against the mycoseshas received scant attention.Therefore, Giuseppe Teti (Uni-versity of Messina, Italy) looked atthe role of type I interferons incryptococcosis. Mice deficient ineither IFNbeta or the IFNal-fa/beta receptor had reduced sur-vival in a pulmonary challengemodel. Small, but significant,amounts of IFNalfa were pro-duced by macrophages after cryp-tococcal stimulation.

Two speakers selected from thesubmitted abstracts finished thesession. Kirsten Nielsen (Universi-ty of Minnesota, Minneapolis,USA) examined the role ofpheromone signaling during in vi-vo infection. In a co-infectionmodel, she studied disseminationof a and alfa strains that had dis-rupted pheromone signaling. Thea cells were increased in size andhad decreased central nervous sys-tem penetration. Finally, HansongMa (University of Birmingham,UK) presented data positively cor-relating virulence of C.neoformansand C. gattii with the capacity toproliferate intracellularly inmacrophages. Interestingly, strainsisolated from the Vancouver Islandoutbreak were amongst the mostrapid intracellular replicators.

Stuart Levitz

The session opened withTamara Doering (Washing-

ton University Medical School, St.Louis, USA) who presented a twopart talk. First, she asked the funda-mental question, “Where is capsulemade?”. Using a conditional mu-tant that doesn’t secrete, accumula-tion of vesicles containing the majorcapsular polysaccharide, GXM, wasobserved, suggesting that at leastthe building blocks are manufac-tured inside the cell. Next, Dr. Do-ering tackled the question of howxylose gets incorporated into thecapsule. A mutant deficient in cryp-tococcal xylosyltransferase 1 (Cxt1)had modestly reduced xylose inGXM but markedly reduced xylosein GalXM. Guilhem Janbon (Insti-tut Pasteur, Paris, France) then dis-cussed galactose metabolism in C. neoformans. He found thatUDP-glucose epimerase 1 (UGE1),but not UGE2, was necessary forvirulence. Moreover, UGE1 is tem-perature regulated, raising thequestion of whether it is part of thestress response.

The next speaker, JenniferLodge (Saint Louis UniversitySchool of Medicine, USA), dis-

West Meets EastA report of the epidemiology and clinical manifestationsof cryptococcosis in the Far East, Europe, the UnitedStates and Australia

Presentations in this session al-lowed a comparison of the sim-

ilarities and differences in cryptococ-cosis in China (Jianghan Chen andZhu Yanjie), Korea (Jun Hee Woo),Japan (Yoshitsugu Miyazaki), Thai-land (Khuanchai Supparatpinyo),South Africa (Tom Harrison), theUSA (Peter Pappas), France(Françoise Dromer) and Australia(Tania Sorrell), and stimulated discus-sion around clinical questions that arestill unanswered. Selected topics of in-terest are summarized below.

Non-AIDS associated crypto-coccosis is currently much morecommon than that associated withAIDS in China, Japan and Aus-tralia. HIV-associated cryptococco-sis has more than halved in the USand France since the advent of high-ly active antiretroviral therapy. Incontrast, the overwhelming majorityof cases in Thailand and South

Africa remain HIV-associated.Though the incidence in Thailandhas declined since the introductionof HAART, cryptococcosis is stillthe third commonest opportunisticinfection in HIV-infected patients.In South Africa, despite the roll-outof antiretroviral therapy programs,many patients with HIV present latewith low CD4 counts, hence the in-cidence of cryptococcosis appearslittle changed. In fact Cryptococcusneoformans is the commonest causeof adult meningitis in areas of highHIV seroprevalence, especially inSouthern and East Africa. Amongother classical causes of immuno-compromise, solid organ transplan-

cussed the fungal cell wall, of whatis “underneath the capsule”. Sheemphasized that C. neoformans isknown to have alfa-1,3-glucans, be-ta-1,3-glucans, beta-1,6,-glucans,>50 predicted GPI-anchoredmannoproteins, chitin and chitosan.Unknown still is whether C. neofor-mans makes beta-1,4-glucans. Agenome-wide search for putativeenzymes involved in cell wall syn-thesis reveals 8 chitin synthases, 3chitin synthase regulators and 4chitin deacetylases. The function ofeach and the reason for this appar-ent redundancy are being exploredby making deletion strains.

Two speakers chosen from thesubmitted abstracts concluded thesession. Michael Botts (Universityof Wisconsin-Madison, USA)demonstrated a new density gradi-ent technique which yielded ba-sidiospores that were 90% viable.As basidiospores are postulated by

Cell Wall and Capsule7th ICCCNagasaki, Japan

11-14 September 2008

Simon Johnston Kazuyoshi Kawakami

Giuseppe Teti

Tania Sorrell

several speakers spoke to their clin-ical impression that outcomes aresignificantly worse in patients withcirrhosis, due largely to poor toler-ance of the best therapeutic regi-mens in this group. More work toelucidate optimal therapy is re-quired.

There was a consistent findingthat abnormal mental status at pre-sentation is associated with a worseoutcome regardless of therapy. Itwas of interest to hear that 22% ofpatients in Shanghai present withoptical disease, significantly higherthan in Western countries repre-sented. A similarly high rate of pa-pilloedema/optic neuritis was re-ported from Papua New Guinea pri-or to the AIDS epidemic and wasattributed to a typically late presen-tation of illness. Other statisticallysignificant poor prognostic markersin CNS diseases included underly-ing cirrhosis and high CSF protein(Korea) and CSF cryptococcal anti-gen >512, infection with serotype Arather than D and failure to receive5-flucytosine as part of the induc-tion antifungal therapy (France).

Several delegates raised the pos-sibility that differences in epidemi-ology, clinical features and responsemay result from individual geneticand/or ethnic genotypic differences.There was general agreement thatfurther investigation of host deter-minants is warranted.

Approaches to induction thera-py for cerebral cryptococcosis var-ied depending on the availability ofdrugs in different countries. In thosewhere amphotericin B and 5FC areavailable this combination was gen-erally considered to be the treat-ment of choice. In organ transplantrecipients in the US, liposomalAMB is preferred to conventionalAMB because of the high risk of re-nal failure in this group. In Thai-land, where 5FC is not available andmost cases are associated withAIDS, an initial 2-week course ofAMB is followed by 400mg/d of flu-conazole for 8 weeks and thenmaintenance fluconazole therapy isused. The high prevalence of cryp-tococcosis and HIV co-infection inThailand is the rationale for theunique recommendation that pri-mary prophylaxis be given. Itra-conazole, which is also effectiveagainst another problematic oppor-tunistic fungus in Northern Thai-land, Penicillium marneffei, is rec-ommended for those with a CD4lymphocyte count <100.

Two speakers, Zhu Yuanjie andTania Sorrell, emphasized the pro-longed time that more than one ofCSF glucose, leukocyte count, IndiaInk stain and cryptococcal antigentitre remain positive, even with suc-cessful therapy. It can be concludedthat a better means of monitoringthe therapeutic response to allowindividual optimization of therapeu-tic regimens is needed.

Tania C. Sorrell

Special report

tation is now of particular impor-tance (but not haematopoietic stemcell transplantation). In the US,cryptococcosis is the third common-est invasive fungal infection in re-cipients of solid organ transplants,often presenting more than 12months post- solid organ transplan-tation.

C. neoformans serotype A is thepredominant pathogen in all coun-tries. In Australia, where infectiondue to C. gattii is endemic and af-fects apparently healthy individuals,approximately half of the cases inthis group are still caused by C. neo-formans, whereas in other countriesreporting C. gattii infection, the pro-portion of cases in HIV-negative in-dividuals is lower. Notably, datafrom British Columbia, Canada,which is the site of the most recentoutbreak of cryptococcosis due toC. gattii, were not presented in thissession. In France, serotype D caus-es a significant minority of casescompared with serotype A but is in-frequent outside of Europe.

A number of presenters notedthat cirrhosis/chronic liver disease,diabetes mellitus and/or end-stagerenal disease were present in a sig-nificant number of non-AIDS asso-ciated cases, though in the absenceof case control or prospective stud-ies it was not always clear that theseconstituted independent risk factorsfor cryptococcosis. Nevertheless


Gene Regulation and Signaling

Two sessions on gene regulationand signaling highlighted the

complexities of the signaling pathwaysin Cryptococcus neoformans. Forexample, a host-specific signal likeelevated temperature leads to amyriad of responses including al-tered shape, size and volume. An-drew Alspaugh (Duke UniversitySchool of Medicine, USA) present-ed nice data demonstrating that thedifferential localization of Ras1, ei-ther to the cell surface or to en-domembranes, may represent amechanism by which C. neoformansRas1 can specifically activate dis-tinct signaling pathways in responseto different upstream signals. PingWang (Louisiana State UniversityHealth Sciences Center, New Or-leans, USA) showed that Crg2, aregulator of G protein signaling inC. neoformans functions as a multi-regulatory protein that controlsmating distinctly from Crg1 and alsoinhibits Gpa1-cAMP-dependentsignaling. Among the repertoire ofresponses to different stresses is acalcium-mediated signaling path-way that promotes survival of C. neoformans to ergosterol biosyn-thesis inhibitors. Angie Gelli (Uni-

Special report

Khuanchai Supparatpinyo

7th ICCCNagasaki, Japan11-14 September 2008

versity of California, USA) present-ed evidence demonstrating that thecalcium channel Cch1-Mid1, a cen-tral mediator of this pathway is acti-vated by the depletion ofER/secretory calcium stores anddemonstrated the possibility of iden-tifying inhibitors of Cch1-Mid1 thatcould function to promote fungicidalactivity of ergosterol inhibitors suchas azoles. Interestingly and perhaps

not surprisingly some signaling path-ways may operate differently in C. gattii. Sudha Chaturvedi (Wads-worth Center, USA) presented evi-dence suggesting that several genesin C. gattii involved in oxidativestress, mating and secretion appearto be functionally and structurallydifferent when compared to thesame genes in its sibling species, C. neoformans. These unique differ-ences between similar sets of genes

could constitute diverse virulencemechanisms in C. gattii.

Studies in cell signaling wouldbenefit enormously from more ge-netic and biochemical tools such asthe ones being developed by HitenMadhani’s group (University of Cal-ifornia-San Francisco, USA).Among the newest developmentsare DNA tiling microarrays for C. neoformans. These arrays go be-yond the measurement of mRNAexpression levels because they canuncover characteristics of large-scalechromosome function and dynamicsas well as promote discoveries ofregulatory pathways. The usefulnessof genome-wide approaches thatidentify and characterize global pat-terns of gene expression was evidentin the nice work presented by JimKronstad (University of British Co-lumbia, Canada) where he discussedthe use of combined transcriptionalprofiling by serial analysis of geneexpression (SAGE) and DNA mi-croarray analysis in understandingthe role of iron as a regulator of vir-ulence factor expression and as acentral nutrient during infection.DNA microarrays were also used tostudy the mechanism of heteroresis-tance in C. neoformans. In work pre-sented by June Kwon-Chung (NI-AID, NIH, Bethesda, USA), tran-scriptome comparisons betweenH99 and clones resistant to flucona-zole revealed several hundred genesthat were upregulated in the resis-tant subpopulations. Many of thedifferentially regulated genes werelocated on chromosome A and Land both chromosomes were dupli-cated in resistant clones. Heterore-sistance appears to be independentof Hog1 signaling, unlike the cellularresponse to other types of stresses.

Angie Gelli

Angie Gelli

Jim Kronstad June Kwon-Chung

Andrew Alspaugh (right) and Guilhem Janbon


novel work on the interaction be-tween cryptocccal cells and those ofStaphylococcus aureus. Coculturingwith S. aureus resulted in killing ofcryptococcal cells. This mechanismseems dependent on the biochemi-cal composition of the cryptococcalcapsule and the presence oftriosephosphate isomerase (TPI)present in the cell wall of S. aureus.Following adherence of S. aureus,

apoptosis-like celldeath is induced in C. neoformans cells.Massimo Cogliati(University of Milan,Italy) presented dateon a novel sero-type C population of C. gattii that belongedto genotype VGIV inIndia. Using MultiLocus Sequence Typ-ing (MLST) analysisthe Indian isolates

could be linked to a population inBotswana.

In a presentation on behalf ofseveral South American colleagues,Elisabeth Castañeda (UniversidadEl Bosque, Bogota, Colombia) pre-sented evidence on the presence ofthe VGII genotype of C. gattii(6.2% of the isolates) in SouthAmerica, especially in the Amazonarea in Brazil and in Colombia.Both C. neoformans var. grubii and


Epidemiology,Molecular Typing,Population GeneticsAnumber of presentations illus-

trated the recent advancesmade in the fields of taxonomy, epi-demiology, molecular typing andpopulation genetics. In a summarizingpresentation Teun Boekhout (CBSFungal Biodiversity Centre, Utrecht,The Netherlands) described the pres-ence of six monophyletic lineages pre-sent within the Cryptococcus neofor-mans species complex that may rep-resent separate species.Based on nuclear genesthese lineages werefound to be geneticallyisolated, but apparentlyrecombination has beenobserved to be presentin C. gattii in some mito-chondrial genes. More-over, interspecific C. neoformans x C. gattiihybrids were discussed.Dee Carter (Universityof Sidney, Australia) ad-dressed the issue of sexual recombi-nation in C. neoformans. MostCryptococcus populations show ahighly unbalanced mating type ra-tio, yet the infectious agent isthought to be a sexually generatedbasidiospore. Intererestingly, re-combining populations were ob-served to occur by analyzing smallclusters of isolates occurring on phy-lograms based on AFLP analysis. C. neoformans isolates belonging tothe VNI and VNII genetic types iso-lated from small animals in the Syd-ney region, showed recombination.Apparently, recombination occursin the environment in both C. neo-formans var. grubii and C. gattii.Reiko Ikeda (Meiji PharmaceuticalUniversity, Japan) presented her

During the last two decades wehave learned much about the

pathogenesis of cryptococcosis and yetthe understanding of the molecularmechanisms of pathogenicity of Cryp-tococcus neoformans in the contestof the status of the host immune re-sponse is only very recently takenunder consideration. There is now aconsensus that the virulence factorsof C. neoformans are not static com-ponents of its pathogenic fitness butrather fungal features that changedynamically during the infectionperhaps according to the host envi-ronment in which the fungus is lo-cated.

The session on “Virulence fac-tors”, have shed some light on possi-ble mechanisms by which this fun-gus adapts to host environments.

Peter Williamson (University ofIllinois at Chicago, USA) talkedabout the autophagic process of C.neoformans and suggested that, dur-ing starvation conditions in the host,autophagy may allow the fungus tosurvive within host macrophages (1).The intracellular compartment is anutrient deprived environment andC. neoformans responds by inducingmechanisms, such as the autophagicprocess, that would allow it to grow.

Virulence Factors

C. gattii were detected on variousspecies of trees. Jianghan Chen(Second Military Medical Universi-ty, Shanghai, China) reported onthe high incidence of C. neoformansvar. grubii among apparently im-munocompetent patients in China.Anastasia Litvintseva (Duke Uni-versity Medical Center, Durham,USA) presented a highly interestinghypothesis suggesting that genotypeVNB and VNI-B isolates of C. neo-formans var. grubii originated inSouthern Africa, where they occupy

a specific ecological niche, especial-ly related to the mopane (Colophos-permum mopane) tree. VNI iso-lates, in contrast, seems to be im-ported in Africa by migration of hu-mans and/or birds (especially pi-geons). Different subpopulations ofVNB are geographically isolated,they show recombination within theenvironment, and hybridization oc-curs between strains of VNI andVNB. Finally, Wieland Meyer (Uni-versity of Sidney, Australia) showedhis results of an ongoing effort tostudy the global molecular epidemi-ology of the C. neoformans speciescomplex. Using PCR-fingerprintingand MLST eight major moleculartypes were observed, including twosubtypes in C. grubii and theserotype AD hybrids. In addition,evidence was presented that thehigh and low virulent genotypesVGII-A and VGII-B also occur inSouth America, and that these maybe ancestral to the Australasianpopulations as well as the popula-tion causing the Vancouver Islandoutbreak.

Teun Boekhout


Teun Boekhout

Reiko Ikeda Elisabeth Castañeda and David Ellis

Massimo Cogliati (left) and Wieland Meyer

Anastasia Litvintseva


Interestingly, this process may alsofavor the survival of the fungus with-in macrophages during the latent in-fection.

Bettina Fries (Albert-EinsteinCollege of Medicine, USA) talkedabout the phenotypic switching ofC. neoformans and its contributionto virulence (2). During infection,this fungus can undergo reversibleswitching from a smooth parent to amucoid variant. Interestingly, themucoid is more virulent than thesmooth variant. Dr. Fries identifiedtwo genes (ALL1 and ALL2) thatare downregulated in the mucoidvariant and, thus, deletion of thesegenes significantly enhanced viru-

Maurizio Del Poeta

Tamara Doering and Joe Heitman


lence. Studies addressing how thesegenes are regulated during the in-fection are underway.

Julianne Djordjevic (Universityof Sidney, Australia) talked aboutcryptococcal phospholipases andthe fungal secretory pathway (3).This pathway is essential for makingan intact cell wall, capsule and ex-porting key virulence factors, suchas laccase and phospholipase B1.Dr. Djordjevic has identified fungalproteins such as phosphatidylinosi-tol-specific phospholipase C (PI-PLC) and potentially beta glucanas-es, as key regulators of the secretorymechanism and the establishmentof cryptococcal cell wall integrity.

Finally, my talk was about themathematical modeling of crypto-coccal pathogenicity (4). We recent-ly created a mathematical model ofthe Cn sphingolipid pathway withinthe framework of the BiochemicalSystem Theory (BST), which usespower-law representations for enzy-matic and transport processes (5-7).


Bettina FriesJulianne Djordjevic

Tissue Tropism7th ICCCNagasaki, Japan


The studies presented at the TissueTropism session explored differ-

ent mechanisms by which cryptococciare enabled to persist in the lung, and togain access to the brain and survive with-in the CNS. The opening talk by Am-brose Jong (Keck School of Medicine,Los Angeles, USA) revealed an excitingmechanism that could contribute to highcryptococcal CNS tropism. His studiesexplored the concept of blood brain bar-rier invasion in the context of a direct in-teraction of brain microvascular en-dothelial cells with hyaluronic (HA)present in Cryptococcus neoformanscapsule. These studies reveled a re-lationship between HA synthesis byC. neoformans, HA retention in thecryptococcal capsule and the en-gagement of HA with host’s CD44molecules to achieve firm adhesionbetween the organism and the host’s

endothelial cell. Furthermore, theinteraction of HA with CD44 trig-gered signaling pathway that lead tophosphorylation of protein kinasealpha, down-stream recruitment ofbeta-actin to the endothelial mem-brane rafts and their rearrangement.Dr Yong proposed that C. neofor-mans exploits this pathway, to trans-verse across the endothelium in a“zipper like” fashion following firmadhesion to the endothelial cell sur-face.

Françoise Dromer (Institut Pas-teur, France) presented evidencefor another mechanism of C. neo-formans crossing from blood intothe brain. In a series of elegantstudies she demonstrated that C. neoformans can exploit mono-cytes to cross blood brain barrier asa “passenger” carried by these cells.The proof for this “Trojan Horse”hypothesis was demonstrated bycomparing intravenous inoculationsof the yeasts in a free form with in-jections of yeasts that were ingestedby cultured monocytes. Inoculationof the “Trojan Horses” enhancedfungal burden in the brain, whilethe sustained phagocyte depletionfrom the blood decreased the rateof cryptococcal blood to braincrossing in this model.

The role of cryptococcal viru-lence factor urease on pulmonarygrowth of C. neoformans and dur-ing CNS invasion was demonstrat-ed by Michal Olszewski (Universityof Michigan, Ann Arbor, USA).Studies of his group demonstratedthat urease expression enhancescryptococcal persistence in thelungs, by potentiating the non-pro-tective Th2-arm of the T cell medi-

ated immune response. Deletion ofurease gene from C. neoformans re-sulted in a 100-fold decrease in lungburden, reduced Th2 cytokine ex-pression/IgE production, and an ab-sence of the Th2-driven pathologyin the lungs of C57BL6 mice. Fur-thermore, this study suggested thatdentritic cells are the upstream cel-lular target of urease-mediated vir-ulence, as urease expression in-creased the frequency of immaturedentritic cells in regional pul-monary lymph nodes. Dr. Olszews-ki also presented evidence that ure-ase enhances blood-to-brain inva-sion by enhancing C. neoformanssequestration within small capillar-ies. These studies provided evi-dence that urease acts as virulencefactor in both pulmonary and mi-crovascular compartments, andthus promotes cryptococcal tissuetropism in both the lung and brain.

Lung and brain tissue representextreme conditions in the host en-vironment with respect to oxygenconcentration. Metabolic shift fromthe growth in high (the lungs) tolow oxygen conditions (brain) is re-quired for cryptococcal brain inva-sion. Yun Chang (NIH, Bethesda,USA) explored genetic basis of C. neoformans adaptation to lowoxygen environment using geneticscreening of T-DNA insertionalmutants. Multiple pathways thatenabled C. neoformans growth inlow oxygen levels have been identi-fied, including genes regulating er-gosterol biosynthesis, iron home-ostasis, as well as mitochondrialfunctions and sensitivity to reactiveoxygen species.

In summary, studies presented at

the Tissue Tropism session of 7thICCC, highlighted the progress inour understanding of mechanismsthat contribute to the pathogenesisof cryptococcal infection. Some ofthese mechanisms, in particular the“Trojan Horse” hypothesis and thehypothesis for a direct interaction ofC. neoformans with brain endothe-lial cells during CNS invasion wereinitially proposed as alternatives.However, the data presented at thisconference were not conflicting.Both mechanisms were convincinglyshown to be used by C. neoformansin different clinical circumstances.Future studies are likely to deter-mine whether cryptococcal ureaseand the genes important in hypoxicconditions are important for C. neo-formans survival in the "TrojanHorse" monocytes. These genescould also contribute to CD44 de-pendent and CD44-independent in-teractions of C. neoformans with thecerebral endothelium. In the future,we expect to learn about new cryp-tococcal genes and new mechanismsthat aid C. neoformans persistencein the lungs and its CNS invasion.These studies will deepen our under-standing of cryptococcal pathogene-sis and provide a new opportunityfor the development of novel thera-peutic strategies.

Michal Olszewski

Michal Olszewski

Françoise Dromer Yun Chang

References

1. Hu, G., M. Hacham, S. R.Waterman, J. Panepinto, S. Shin, X. Liu, J. Gibbons, T. Valyi-Nagy,K. Obara, H. A. Jaffe, Y. Ohsumi,and P. R. Williamson. 2008. PI3Ksignaling of autophagy is requiredfor starvation tolerance andvirulence of Cryptococcusneoformans. The Journal of clinicalinvestigation 118:1186-1197.

2. Jain, N., L. Li, Y. P. Hsueh, A. Guerrero, J. Heitman, D. L.Goldman, and B. C. Fries. 2008.Loss of Allergen1 (ALL1) confers ahypervirulent phenotype thatresembles mucoid switch variants ofCryptococcus neoformans. Infectionand immunity.

3. Siafakas, A. R., T. C. Sorrell, L. C. Wright, C. Wilson, M. Larsen,R. Boadle, P. R. Williamson, and J. T. Djordjevic. 2007. Cell wall-linked cryptococcal phospholipaseB1 is a source of secreted enzymeand a determinant of cell wallintegrity. The Journal of biologicalchemistry 282:37508-37514.

4. Garcia, J., J. Shea, F. Alvarez-Vasquez, A. Qureshi, C. Luberto,E. O. Voit, and M. Del Poeta. 2008.Mathematical modeling ofpathogenicity of Cryptococcusneoformans. Molecular SystemBiology 4:183-195.

5. Savageau, M. A. 1969. Biochemicalsystems analysis. II. The steady-state solutions for an n-pool systemusing a power-law approximation. J Theor Biol 25:370-379.

6. Savageau, M. A. 1969. Biochemicalsystems analysis. I. Somemathematical properties of the ratelaw for the component enzymaticreactions. J Theor Biol 25:365-369.

7. Torres, N. V., and E. O. Voit. 2002.Pathway analysis and optimizationin metabolic engineering.Cambridge University Press,Cambridge, UK.

On the basis of predictions using themathematical model empirical re-sults, we were able to study and val-idate the changes in the sphingolipidpathway when C. neoformans cellsswitches form the extra- to the intra-cellular environment and to pro-pose new mechanisms of intracellu-lar adaptation.

Maurizio Del Poeta

that treatment outcomes tend to bebetter among immunocompromisedcompared to otherwise normal indi-viduals.

Peter Pappas, from the Universityof Alabama at Birmingham, dis-cussed cryptococcosis among trans-plant recipients. Most of Dr. Pappas’discussion focused on the results ofTRANSNET, a prospective surveil-lance program among 25 US trans-plant centers, which was conductedbetween 2001 and 2006. During thattime, 98 cases of transplant-associatedcryptococcosis were identified. Dr.Pappas underscored the importanceof this infection among solid organtransplant recipients and indicatedthat three-month mortality for thisdisorder was approximately 25%,among the lowest of the invasive fun-gal infections in this vulnerable popu-lation. He emphasized that cryptococ-cosis remains an important complica-tion in the late post-transplant periodin solid organ transplant recipients.

Tania Sorrell, from the Universi-ty of Sydney, discussed cryptococcalphospholipase B as a potential anti-fungal drug target. Cryptococcalphospholipase B1 facilitates invasionof the lung and is essential forhematogenous dissemination of in-fection. Using structure-activity rela-tionship experiments, the author at-tempted to correlate antifungal activ-ity of several compounds through in-hibition of phospholipase B1. Inter-estingly, miltefosine, an anti-proto-zoan agent with broad-spectrumfungicidal activity, inhibited phos-pholipase B1 activity, but only atconcentrations greater than six timesthe MIC, suggesting that phospholi-pase B1 inhibition is not its primarymode of action. Other compoundsdemonstrated significant antifungalactivity, but this was restricted toyeasts. The most promising of thesecompounds was miltefosine.

Peter G. Pappas

Second Session

John Bennett (NIAID,Bethesda, USA) opened the

session by providing a historicaloverview of clinical trials incryptococcal meningitis (CM),and outlining key gaps in ourknowledge of its management.The evidence of the need for asecond drug (5FC) in combina-tion with amphotericin B was re-viewed, as well as the timing ofswitch to, and best azole to useas maintenance therapy. Moreinformation is required on theoptimal treatment of raised CSFopening pressure and the idealtime to start antiretroviral ther-apy post diagnosis of CM, aswell as better definitions andguidelines for management ofcryptococcal immune reconsti-



This session contained talksabout micro evolutionary

events, sexual reproduction inCryptococcus and related species,and sexual development. JamesFraser (University of Queensland,Brisbane, Australia) gave an in-triguing talk on the role of sub-telomeric regions in evolution andadaptation to new environments.Cryptococcus has karyotypic varia-tion from strain to strain and re-lapse infections often display grosschromosomal rearrangements.Translocations, duplications, inver-sions, and deletions could provide aselective advantage, but would like-ly lead to sterility. Changes in sub-telomeric regions would allow sub-tle changes that are tolerated dur-ing sexual development. Examina-tion of sub-telomeric regions re-vealed genes associated with nicheadaptation. The Fraser lab hascharacterized one of these regionson the right arm of chromosome 3that contains many hexose trans-porters. They observed amplifica-tion of the arsenic transporter geneARR3 with 3-18 copies of the gene.Arsenic is a toxic metalloid that ispumped out of cells by ARR3.Analysis of arsenic resistance re-vealed that strains with increasedARR3 gene copy number had high-er resistance.

Joe Heitman (Duke UniversityMedical Center, Durham, USA)presented a fascinating talk on thestructure and evolution of the mat-ing type locus in Cryptococcus andclosely related species. Cryptococ-cus is a member of the basid-iomycete phylum. Most basid-iomycetes have a tetrapolar matingsystem with two unlinked loci. YetCryptococcus has a bipolar matingsystem with only a single locus.Analysis of this locus suggests it was

Special report

Sex, Mating, and Evolution


Kirsten Nielsen

James Fraser Joe Heitman

generated by fusion of two loci. Tobetter understand the mechanism ofthe evolution of the MAT locus, theHeitman lab has cloned and ana-lyzed the mating loci from otherclosely related species. By charac-terizing the mating loci in C. amylo-lentus they have been able to identi-fy strains of opposite mating typeand characterized mating for thisspecies. In addition, Dr. Heitman al-so presented additional data sup-porting the prevalence of same-sexmating in the environment andshowed that it may be linked to aspecific Sxi1alpha phenotype.

Emilia Kruzel from ChristinaHull’s lab (University of Wisconsin-Madison, USA) presented an ele-gant study to characterize gene ex-pression during sexual developmentusing microarray analysis. Theyidentified early, intermediate, andlate genes and also found spatial dif-ferences in expression of manygenes known to be involved in mat-ing. For example, pheromone geneexpression was up-regulated earlyin the mating process and then re-pressed later in sexual develop-ment. They also identified a class ofunknown genes which may be in-volved in dikaryotic growth.

There were also a few talks in

other sessions which relate to sex,mating, and evolution. Dee Carter(University of Sydney, Australia)described population genetic stud-ies which show evidence of recom-bination and same-sex mating inlimited geographic or temporalranges suggesting that sex and sporeproduction are probably common inthe pathogenic Cryptococcusspecies but may be masked by clon-al expansion. Kirsten Nielsen (Uni-versity of Minnesota, Minneapolis,USA) showed coinfection with bothmating types blocks central nervoussystem penetration by one of thesexes in a pheromone dependentmanner. The pheromone signalingresults in giant cell productionwhich may alter host cell interac-tions to affect virulence. Finally,Michael Botts, from the Hull lab,showed that spores are more resis-tant to environmental stresses. Elec-tron microscopy revealed that thespore coat contains capsule whichplays a role in proper sexual devel-opment and spore dispersion. Thesestudies underscore the importanceof sex and evolution in many as-pects of Cryptococcus biology andvirulence.

Kirsten Nielsen

Clinical Sessions7th ICCCNagasaki, Japan


First Session

Robert Larsen, from the Uni-versity of Southern California,

discussed a new method of suscepti-bility testing for Cryptococcus neo-formans and attempts to correlateresults with clinical outcomes. Thefundamental approach to hismethod, which has not been validat-ed in clinical trials, is based on theconcept that quantitative culturesare a useful tool in assessing myco-logic response, and that susceptibili-ty testing should be linked to quan-titative cultures providing more of a“continuum” rather than a simple‘susceptible or ‘resistant’ result. Dr.Larsen has not been able to corre-late these data with clinical out-come, but his hypothesis is that thecurrent method of susceptibilitytesting is somewhat flawed, and thatrelationship between susceptibilitydata and clinical outcome should befurther explored.

Li-Ping Zhu, from Fudan Univer-sity in Shanghai, reported a retro-spective 11-year survey of non-HIVinfected patients who have been di-agnosed with cryptococcal meningi-tis. During this 11-year period span-ning the years 1997 through 2007,154 cases of non-HIV-associatedcryptococcal meningitis were diag-nosed at this institution. Surprisingly,only 27% of patients had significantunderlying conditions. Out of 72 cas-es who underwent CD4 lymphocytetesting, only 25% were found to havecounts >200 cells/mm3. Most patientsreceived initial therapy with ampho-tericin B with or without 5-flucyto-sine, and there was approximately20% mortality at the end of antifun-gal therapy (10 weeks). About 60%of these deaths were attributable tocryptococcal meningitis. The authorsnote that clinical manifestations inimmunocompromised patients wereless severe than their “normal” coun-terparts, and that response to thera-py was significantly higher in im-munocompromised patients thanotherwise normal patients (P =0.046). The mortality was similar forimmunocompromised and normalpatients. Dr. Zhu’s interesting find-ings suggest that the incidence ofnon-HIV-associated cryptococcalmeningitis is increasing in China and

Peter Pappas

Li-Ping Zhu

Congress report


Special report

tution inflammatory syndrome.Previous studies have shown a

relationship between baseline CSFopening pressure and outcome incryptococcal meningitis. TihanaBicanic (St George’s University ofLondon, UK) presented findingsfrom three studies of HIV-associ-ated CM from Thailand and SouthAfrica (n=163), showing that ag-gressive management of raisedCSF opening pressure using re-peat lumbar punctures over thefirst 2 weeks of treatment resultedin no significant differences inmortality at 2 and 10 weeks be-tween patient groups categorizedaccording to baseline openingpressure (<20, 20-30, >30cm H2O).Opening pressure correlated withfungal burden, both at baselineand day 14 of treatment.

Tom Harrison (St George’sUniversity of London, UK) con-centrated on important issues inthe treatment of CM in developingcountries. In phase II studies, rateof clearance or early fungicidal ac-tivity has been shown to be a suit-able marker of treatment re-sponse. Pooled data from studiesin Thailand, Uganda and SouthAfrica (n=262) demonstrate that apoor rate of clearance is indepen-dently associated with mortality at2 and 10 weeks. In places withoutfacilities to administer ampho-tericin B, studies of the best oraltreatment regimen have shownbest rate of clearance and goodtolerability of oral fluconazole at1200mg/day. A study in Malawi iscomparing this dose alone with a

combination with oral flucytosine.Given the high frequency of im-paired conscious level at presenta-tion, earlier diagnosis is para-mount and a collaboration isplanned to develop a urinary cryp-tococcal antigen test for outpa-tient screening. Campaigns to im-prove access to drugs (ampho-tericin B, flucytosine) and CSFmanometers are ongoing.

Peter Pappas (University of Al-abama at Birmingham, USA) pre-sented the findings from an open-label phase II randomized study ofCNS cryptococcosis conducted inThailand and USA (n=140), com-paring amphotericin B at 0.7mg/kg alone versus in combinationwith fluconazole 400 or 800mg/d

Tihana Bicanic

Tom Harrison John Bennett

Eddie Byrnes representingthe Heitman laboratory

from Duke University opened thesession with a discussion on thevariation within the Cryptococcusneoformans var. grubii type strainH99. Gaining insights into C. neo-formans var. grubii virulence mech-anisms and genomic architecturethrough a detailed analysis of pas-saged H99 isolates. Since the“birth” of isolate H99 on February14th, 1978 many things have hap-pened. The isolate lost virulencethrough lab passage (possibly mul-tiple independent times), was pas-saged through a rabbit to increasevirulence, and distributed globallyto many labs. Some version of thisisolate was used to sequence thegenome, construct a congenicstrain pair (KN99a/alfa), constructlarge-scale mutant libraries (Mad-hani/Lodge), and most recentlyused to construct a tiling array.This has been the major type strainfor serotype A, and has been usedin countless publications over thelast 2 decades. Acknowledging andunderstanding the differences be-tween these passaged isolates, andincreasing awareness of isolatechoice for experiments is importantfor many future studies. To exam-ine differences in phenotype andgenotype, we are conducting classi-cal genetic experiments with mat-ing and artificial diploid construc-tion, comparative genomic hy-bridizations with NimbleGen(Heitman and Kronstad), cDNAmicroarray studies in YPD, CSF,and L-DOPA medias (Perfect andHeitman), murine virulence exper-iments (Lodge), and whole genomesequencing of several variants withsingle and paired end Solexa se-quencing (Dietrich). It is our goalthat this focus will allow a greaterunderstanding of genetic, and pos-sibly epigenetic determinants ofvirulence, and mating.

Jim Kronstad from the Univer-sity of British Columbia followedwith a description of analysis of theC. gattii genomes. He utilized com-parative genome hybridization(CGH) to compare gene copynumber among gattii isolates with

Genomics Workshop


Jennifer Lodge

Eddie Byrnes

different virulence. Althoughchanges in copy number were seen,there was not a clear correlationbetween virulence and a specific lo-cus. CGH analysis of serotype Astrains also revealed a large num-ber of changes so that it is difficultto pick out specific changes to test.Disomy of chromosome 13 may berelatively common, and may resultin lack of melanization.

Cheryl Chun from the Madhanilaboratory at University of Califor-nia, San Francisco, then describedthe high throughput gene deletionproject. The lab generated over1200 deletion strains, and thesewere tested in vitro and in vivo us-ing a mixed model of infection.They found 164 strains with defectsin growth in the lung. Many ofthese strains have defects in growthat 37°C, melanin or capsule, but ap-proximately one fourth have noknown defects, and may representnovel mechanisms. She also de-scribed a putative transcription fac-tor, GAT201, that may regulatemany of genes involved in viru-lence. The Madhani lab gene dele-tion set is available from the ATCCand the Fungal Genetics StockCenter.

Kim Gerik from the Lodge lab-oratory at Saint Louis Universitydescribed a bioinformatics ap-proach to identifying signalingcomponents for the cell integritypathway. She and colleagues haveidentified 25 potential signal trans-duction proteins through domainsearches. Gene deletions haveidentified ten potential candidatesthat could be responsible for signaltransduction of stresses includingcell wall stress as well as oxidativeand nitrosative stress. The Lodgelab gene deletion set is availablefrom the Fungal Genetics StockCenter.

Tamara Doering from Washing-ton University described progressby the microarray consortium. Ar-rays with C. neoformans var. neo-formans genes have been availablethrough the Washington UniversityGenome Center since 2005. Manyof the probes also hybridize to var.grubii genes. Now that the annota-tions for the var. grubii strain H99have been updated, the arrays arecurrently being augmented withprobes specific for H99, as well asmating type loci genes, and addi-tional var. neoformans probes. Theprobes are ready for printing, and anew .gal file generated by SteveGiles in Christina Hull’s laboratoryis available. The Broad will be re-leasing a new annotation of H99soon.

for 14 days, followed by mainte-nance fluconazole. All three armswere well tolerated. At day 14,successful outcome (compositeclinical/ mycological endpoint)was seen in 41%, 27% and 54% ofpatients in the 3 arms respectively.There was a trend towards betteroutcomes in the combination armsat 6 and 10 weeks. The resultsshould be validated in a phase IIItrial.

The ensuing discussion focusedon the need for collaborative in-ternational efforts and mobiliza-tion of political will and funding toaddress the above questions, prob-ably in the form of a Phase III tri-al including both developed anddeveloping countries, coupledwith primary prevention in theform of antigen screening and tar-geted primary fluconazole prophy-laxis.

Tihana Bicanic

Special report

assemble since the sequence readsare so short. He described an ap-proach that he is applying to thefungal pathogen of cotton, Ashbyagossypii, which utilizes paired endreads and improves assembly.

Sarah Brown from the Lodgelaboratory at Saint Louis Universi-ty described a proteomic approachto examining the response to ox-idative stress in Cryptococcus.There were very few changes in theCryptococcus proteome induced byexposure to oxidative stress com-pared to the response to nitrosativestress.

Overall there was excellentprogress reported on gene dele-tions, analysis of strains with differ-ences in phenotypes, and availabil-ity of microarrays(http://genome.wustl.edu/activity/ma/cneoformans/). C. neoformansdeletion strains sets (UCSF or

SLU) are available through theFungal Genetics Stock Center(http://www.fgsc.net/) at low cost.There was discussion regarding thepressing need for a central data-base to house genomic, annotation,microarray, gene deletion, pro-teomic and other related data.

Jennifer Lodge

24 Mycology newsletter - December 2008 25Mycology newsletter - December 2008Mycology newsletter - December 2008

Teun Boekhout from UtrechtUniversity, provided AFLP andMLST evidence for six distinctmolecular types (VNI/II/B, VNIV,VGI, VGII, VGIII, and VGIV)that likely represent cryptic specieswithin the C. neoformans/C. gattiispecies complex. This evidence isbeing marshaled to support a pro-posal that C. neoformans var. neo-formans and C. neoformans var.grubii be recognized as distinctspecies rather than simply as vari-eties, and similar proposals shouldbe forthcoming assigning fourspecies within C. gattii (VGI, VGII,VGIII and VGIV). Genomic se-quences are currently available forVNI (H99), VNIV (JEC21 andB3501A), VGI (WM276) and VGII(R265) and representatives of eachother lineage (expect the VGIIIAD hybrid lineage) should be ad-vanced for sequencing. In addition,in select lineages it will likely be ad-vantageous to sequence other iso-lates, such as for the VGII Vancou-ver Island Outbreak lineages VGI-Ia major (R265, already available)and VGIIb minor (R272), for ex-ample. In addition, closely relatednonpathogenic species such asCryptococcus amylolentus, recentlydiscovered to have a novel teleo-morphic form (Filobasidiella amy-lolenta) should also be sequencedfor comparisons. This robust ge-nomic database would consider-ably advance the field.

Fred Dietrich from Duke Uni-versity discussed Solexa, the nextgeneration of DNA sequencing.Sequences obtained from Solexasequencing can be problematic to Joe Heitman, Jim Kronstad and Jennifer Lodge

Cheryl Chun Fred Dietrich

Congress report

3rd AdvancesAgainst AspergillosisThe program covered molecular

diagnostics, fungus-host-inter-actions, Apergillus-sinusitis, control-ling Aspergillus in building up to As-pergillus and asthma. The topics pro-vided a huge impetus for basic andtranslational research. Herein wewill give a short overview on select-ed topics.

In the session on ‘Pathogenesisand clinical manifestations in differ-ent hosts’ Brahm Segal (RoswellPark Cancer Institute, USA) fo-cused on the role of Aspergillus inchronic granulomatous disease(CGD). He explained that CGD isan inherited disorder of theNADPH oxidase complex in whichphagocytes are defective in generat-ing superoxide anion. As a result ofthe defect in this key host defensepathway, CGD patients suffer fromrecurrent life-threatening bacterialand fungal infections. Invasive as-pergillosis is the most importantcause of mortality in CGD. He un-derlined also, that there exists im-portant differences between invasiveaspergillosis in CGD compared toother immunocompromised condi-tions. In neutropenic patients, inva-sive pulmonary aspergillosis is char-acterized by hyphal angioinvasion,coagulative necrosis and paucity ofinflammatory cells. In contrast, an-gioinvasion is not a feature of inva-sive aspergillosis in CGD patients.CGD is also characterized by exces-sive inflammatory responses that areindependent of the host defensedeficit. These findings demonstratea key role of NADPH oxidase indownregulating inflammation in-duced by specific ligands ofpathogen recognition receptors. Re-cent studies point to defective tryp-tophan catabolism underlying im-paired host defense and pathogenicinflammation in CGD. Moreover,Dr. Segal pointed out that prophy-laxis with a mould-active agentshould be offered to CGD patients.Itraconazole was safe and effectiveas prophylaxis in a randomizedstudy. Bone marrow transplantationis curative in CGD, but is associated

Report on...

with expected frequencies of trans-plant-related morbidity and mortali-ty.

Dimitrios P. Kontoyiannis (Uni-versity of Texas, Usa) gave anoverview on invasive aspergillosisand steroid-treatment. He reportedthat glucocorticosetroids (GCs)have pleiotropic effects on the im-mune system that account for thepropensity of patients to potentiallylife-threatening invasive aspergillo-sis (IA). In addition, GC might en-hance the "fitness" of the fungus tocause disease. Although the exactprevalence and attributed mortalityof IA in GC-treated patients is diffi-cult to assess, Aspergillus species aresignificant pathogens in patientswith multiple myeloma, collagenvascular diseases, solid organ and es-pecially allogeneic stem cell trans-

plant recipients. In the latter setting,he told, high cumulative doses ofGCs administered for graft-versus-host disease (GVHD) prophylaxisand/or treatment have been shownto be associated both with the risk ofacquisition and the poor outcome ofIA. There are distinct differences inthe histopathologic features of inva-sive pulmonary aspergillosis in GC-induced immunosuppression com-pared to IA caused by neutropenia.The lesions in GC-associated IAconsist mainly of neutrophilic andmonocytic infiltrates, inflammatorynecrosis, scant intra-alveolar hemor-rhage and a paucity of hyphae andangioinvasion; in contrast, coagula-tive necrosis, intraalveolar hemor-rhage, scant mononuclear inflamma-tory infiltrate and higher "burden"of invading hyphal elements is ob-served in granulocytopenic animals.Not suprisingly, the performance ofnon-culture based antigen detectiondiagnostic methods is suboptimal inGC-associated IA, because the fun-gal burden is low. He concluded withthe following message: the severityof IA appears to be associated withthe intensity of GC treatment there-fore, every effort should be made to-ward the use of the lowest GC dosefor the shortest possible time.

In the session ‘Aspergillus sinusi-tis’ Arunaloke Chakrabat (Postgrad-uate Institute of Medical Education

The 3rd Advances Against Aspergillosisinternational meeting was in Miami, Florida,January 16-19, 2008. The scientific programproved busy and comprehensive with 13plenary sessions and 3 satellite symposia. Inaddition, two poster sessions were held toaccommodate presentation of the 95 postersaccepted for presentation.


Special report

26 Mycology newsletter - December 2008

& Research, Chandigarh, India) dis-cussed in detail the controversies sur-rounding the categorization of fungalsinusitis. He pointed out that sinusi-tis, more accurately rhinosinusitis, isa common disorder affecting approx-imately 20% world population atsome time of their lives. He statedthat acute rhinosinusitis (ARS) iswell categorized, yet controversiesencompass chronic rhinosinusitis(CRS), especially the fungal rhinosi-nusitis (FRS). Based on histopatho-logical findings, FRS can be dividedinto two categories: the invasive andnon-invasive form, depending on in-vasion of mucosal layer. Three typesof FRS are invasive: acute fulminant,chronic invasive and granulomatousinvasive. The two non-invasive FRSdisorders are fungal ball, and fungusrelated eosinophilic rhinosinusitis (ofwhich allergic fungal rhinosinusitis(AFRS) appears to be a distinct dis-order). Still, categorization of FRSremains controversial and open todiscussion. Especially as it was sug-gested, that fungi might play an im-portant role in CRS. Diversity ofopinion exists on whether FRSshould be characterized as an infec-tion or an inflammatory condition.He pointed out, that currently thereare more questions than answersconcerning the categorization ofFRS. Recognizing the problem sev-eral societies try to reach a consensuson these definitions. ISHAM has al-so formed a working group on ‘Fun-gal sinusitis’ to exchange ideas in thedirection of resolving the problems.

In the session ‘Aspergillus speciesand strain differences’ CorneKlaassen (Canisius Wilhelmina Hos-pital, Nijmegen, The Netherlands)gave on overview on how to best runmolecular typing in Aspergillus. Hestated, that only two molecularmethods available, which are highlyreproducible and yield unambigu-ous, user independent, typing data:the Multi Locus Sequence Typing(MLST) and the microsatelliteanalysis. Each of the two methodsoffers several advantages over theother. The main advantage of MLSTis the DNA sequence format that isaccessible to a growing number ofclinical laboratories. DNA sequencedata are easily compared and ex-

changeable between labs. Yet wehave to know that the costs are high,the turn-around time long and thediscriminatory power relatively low.The latter is a direct consequence ofthe relatively low mutation rate of agiven DNA sequence due to thepresence of mismatch repair mecha-nisms. Microsatellites are unique intheir extremely high discriminatorypower which is a direct result of theinherent instability, during DNAreplication, of tandemly repeatedDNA sequences. Fortunately, mi-crosatellites are still sufficiently sta-ble to allow longitudinal studieswithin an appropriate time window.However, interpretation of genotyp-ically different isolates should bedone with care and should take thisinstability into account. He under-lined, that microsatellites areamendable to rapid and high-throughput analyses in a modularfashion allowing large numbers ofisolates to be analyzed. The cons ofmicrosatellite markers are that theyare species specific. Basically, thechoice for either of the two methodscould be appropriate and should pri-marily be based on the exact reasonfor performing strain typing. Heconcluded that MLST seems to bemost informative at the genus and/orpopulation level whereas microsatel-lites are best used when high-resolu-tion strain typing is required.

In the session ‘T-cell immunity’Teresa Zelante from University ofPerugia, Italy, gave on overview onhost response signatures to invasiveaspergillosis. She spoke on dendriticcells (DCs), which comprise severaldifferent forms or subsets, each hav-ing distinct receptors for antigen up-take and signalling, different path-ways for antigen processing and dif-ferent functional outcomes. In vitrostudies suggested pulmonary DCs tobe able to internalize Aspergillus fu-migatus conidia and hyphae.

She concluded her presentationwith the perspective that theIDO+DCs/Tregs axis has a protec-tive role in fungal allergy and sug-gested that induction of IDO couldbe an important mechanism under-lying the anti-inflammatory action ofcorticosteroids.

In the session ‘Aspergillus growth

towards pathogenicity’ AlessandroPasquallotto (Universidade Federaldo Rio Grande do Sul (UFRGS),Porto Alegre, Brazil) gave on sum-mary on the clinical syndromes dueto A. fumigatus and A. flavus. Hestated that most of the informationavailable about Aspergillus infec-tions has been originated from A. fu-migatus, the most frequent species inthe genus. A. flavus is however par-ticularly prevalent in regions of theworld with dry and hot climate suchas the Middle East and Sudan. Inter-estingly, A. flavus seems more viru-lent and more resistant to antifungaldrugs than most of the other As-pergillus species, which has beendemonstrated both in vitro and inanimal models. He suggested thataflatoxin does not seem to be a ma-jor factor in the pathogenesis of A. flavus infections (A. flavus iso-lates produce aflatoxin B1, the mosttoxic and potent hepatocarcinogenicnatural compound ever character-ized). A. flavus is a common etiologyof fungal sinusitis and cutaneous in-fections, but not fungal pneumonia.Only chronic cavitary pulmonary as-pergillosis has rarely been associatedwith A. flavus. Although A. fumiga-tus is responsible for the vast major-ity of cases of allergic bronchopul-monary aspergillosis (ABPA), A. flavus has also been implicated insome series, mostly in India. Thebigger size of A. flavus spores, incomparison to A. fumigatus spores,may favor their deposit in the upperrespiratory tract. A. flavus also ac-counts for circa 80% of Aspergilluskeratitis cases. Other clinical syn-dromes often linked with A. flavusinclude postoperative wound infec-tions, Aspergillus osteomyelitis fol-lowing trauma or inoculation, andchronic granulomatous sinusitis.Outbreaks of aspergillosis involvingthe skin, oral mucosa, or subcuta-neous tissues are usually associatedwith A. flavus. He stated that mostof these outbreaks have been associ-ated with a single or a few differentstrains, which contrasts with whathas been documented for infectionscaused by A. fumigatus.

Cornelia Lass-Flörl

Congress report

Report on...ECMM has convened three joint symposia withthe International Union of MicrobiologicalSocieties during the XII Mycology DivisionCongress held in Istanbul from 5 to 9 August2008. The symposia focused on Fungal biofilm,on Invasive fungal infections in the intensivecare, and on Zygomycosis. Following thesynopsis of the three symposia are reported

Fungal Biofilm: the New Frontier Chairs: M. Ghannoum, J.P. Latgé

Biofilms are defined as a com-munity of micro-organisms

that are attached to a surface andembedded in an extracellular poly-saccharidic matrix (ECM).Biofilms are particularly importantin human pathology since growingas a multicellular community helpsto colonize the substratum and re-sist external aggressions. Biofilmsformed by the pathogenic yeastsCandida and Cryptococcus neofor-mans on medical devices show anincrease in the MIC50 to almost allantifungals. Filamentous fungi arealso forming biofilms. Recentlymany keratitis with contact lenswere attributed to biofilm forma-tion of Fusarium species. Extracel-lular material surrounding the As-pergillus fumigatus mycelium hasbeen seen during growth in infect-ed tissues or in vitro under staticaerial conditions. This matrix iscomposed of galactomannan,melanin and other componentsspecific to in vivo or in vitro condi-tions. In vitro alfa1,3 glucans, anti-gens and hydrophobins are presentin ECM whereas in vivo, thesecomponents are only cell wall con- Mahmoud Ghannoum and Jean Paul Latgé

stituants, suggesting that ECM invivo is constituted by other fungalcomponents, still unknown, or byhost-made molecules.

C. neoformans biofilm forma-tion is dependent on the presenceof the capsular polysaccharide glu-curonoxylomannan (GXM) andcorrelated with the ability of GXMto bind the devices. The protectivemonoclonal antibodies IgG1MAb18B7 directed against GXM pre-vents the biofilm formation by

complexing the released GXM andinhibiting further cell binding tothe surface. Complexing IgG1MAb18B7 to Bismuth237 damages thebiofilm by penetration of the anti-body through the channels. How-ever, combination therapy withamphotericin B has an antagonisticeffect since the antibody links thecapsule of the cells and preventsthe penetration of the antifungal tothe cells, suggesting that the hostimmune response may contribute

Three ECMM Symposia at the IUMS 2008

Confocal scanning laser microscopy analyses of Fusarium biofilms formed on different soft contact lenses,showing their varying architecture.Fusarium or Candida isolates were allowed to form mature biofilms on different types of contact lenses:(A,G) etafilcon A, (B,H) galyfilcon A, (C,I) lotrafilcon A, (D,J) balafilcon A, (E,K) alphafilcon A, and(F,L) polymacon lenses. Bioflms were stained with ConA and FUN1 dyes, indicating the presence of poly-saccharides and metabolic activity, respectively. (Imamura et al. (2008). Antimicrob. Agents Chemother.52(1): 171-182).

Congress report

The gastrointestinal insults that mayarise as a consequence of ICU man-agement procedures are responsiblefor the vulnerability of these pa-tients to haematogenous dissemina-tion of Candida species, such as C.albicans, C. glabrata, C. tropicalis,that form part of their commensalflora of the gastrointestinal tract.The alteration of the skin barrier, asin the presence of IV lines, favoursthe acquisition of yeasts, such as C.parapsilosis, colonizing the patient’sskin or the hands of the healthcareworkers. In addition, the vascularcatheters, as well as other im-plantable devices, may behematogenous seeded by Candida,such as C. albicans, C. glabrata etc,coming from distant local infection.Formation of biofilm on implantedbiomaterials increases resistance toantifungal agents, protects Candidafrom host defences, and causes fail-ure of devices.

Infections caused by filamen-tous fungi, such as aspergillosis,fusariosis, zygomycosis, are nowknown to occur with increasing fre-quency in patients other than thosewith classical risk factors such asprofound and prolonged granulocy-topenia. Air and water are the mostimportant sources of these infec-tions. Inhalation of spores is thecommon route of infection by As-pergillus. Ventilation systems, cont-aminated air during renovation ac-tivity, water, food and ornamentalplants remain the major reservoir ofAspergillus in hospital setting, al-though a significant number of pa-tients acquires infection before hos-pitalization. Inhalation of spores,ingestion, trauma and non sterilewound dressing or other contami-nated devices may lead to infectioncaused by other filamentous fungisuch as Fusarium and zygomycetes.

Murat Akova analysed the pub-lished randomised clinical trials ofantifungal prophylaxis with flu-conazole in different adult patientpopulations in the ICU. Candida in-fection, as well as Candida colo-nization, occurred less frequently inthe fluconazole group, but no dif-ferences in mortality could bedemonstrated between the treat-ment and placebo group. A shift to-

wards fluconazole-resistant isolateswas not shown in any of the studies.Even according to the most recent-ly published trial, an early empiricaltreatment was not useful. On thecontrary, efficacy and safety of flu-conazole prophylaxis was demon-strated in preterm infants at highrisk of neurodevelopmental impair-ment associated to Candida blood-stream infection. To identify adultpatients who will benefit by an ear-ly treatment, a prediction rule,based only on clinical data or onboth clinical and microbiologicaldata, was set up by different groupsof American and European inten-sivists.

The armamentarium of antifun-gals available to manage the fungalinfections in the ICU setting was re-viewed by George Samonis. Whilelipid and liposomal amphotericin Bcompounds have been the main-stays of treatment for more than 10years, azoles have recently shownconsiderable efficacy. Fluconazoleis effective against most of Candidainfections, voriconazole was provenvery potent against aspergillosisand significantly improved the out-come of this disease. Posaconazoleas well as echinocandins, cover bothCandida and Aspergillus. Unfortu-nately, while treatment options areincreasing, new fungal threats, suchas Fusarium and zygomycetes, haveemerged. Amphotericin B com-pounds and possibly posaconazole

are indicated against these “new”threats. Combinations of antifungalagents are under investigation, butconclusions have not yet beendrawn. Prof Samonis concludedthat the patient in ICU is often toosick for anything to work and theoutcome of the fungal infectionhighly depends on an early diagno-sis and on the recovery of the im-mune function of the patient.

Lena Klingspor, closed the sym-posium reporting the results of thefirst 18 months of the ECMM sur-vey. A total of 420 episodes of deepCandida infection (76% blood-stream infections) were reportedfrom the participating countries,that is 169 from Italy, 88 from Aus-tria, 69 from Greece, 39 from Swe-den and 10-29 from UK, Finlandand Czeck Republic. Most of thepatients (46%) underwent an ab-dominal surgery and 17% a tho-racic intervention. A solid organtransplant was performed in 2.7%of the cases. A total of 78 (19%) pa-tients had repeated surgical inter-ventions. A solid tumour was theunderlying disease in 34% of thepatients and diabetes in 18.3%. C.albicans caused 59% of theepisodes, followed by C. glabrata(15%), C. parapsilosis (13%), C.tropicalis (6%). C. krusei was re-ported as cause of infection in 11cases (3%) and C. lusitaniae and C.dubliniensis in 8 episodes each.Overall crude mortality at day 30was 31%, highest in C. glabrata(40.5%), C. krusei (46%) and C.lusitaniae (50%) infections. A totalof 15% of the patients was undersystemic antifungal prophylaxiswhen Candida infection was diag-nosed. The management of the in-fection consists of fluconazole in52% of the episodes, caspofunginand liposomal amphotericin B in21% and 16%, respectively. Prof.Klingspor concluded outlining thecharacteristics of the typical surgi-cal patient in ICU affected withdeep-seated candidosis: male, >60year old, undergone to abdominalsurgery, presenting several risk fac-tors, not receiving antifungal pro-phylaxis.



Congress report

to drug resistance of biofilmsformed in vivo.

For C. albicans biofilm forma-tion, surface components such asO- and N- mannosylated glycopro-teins (adhesins) are essential. Theypromote the attachment of the fun-gus to a surface. Two MAP kinasesMkc1p and Cek1pand their effec-tors Pmt1p and Pmt4p (O-manno-syltransferases) as well as Efg1pregulator (transcription factor reg-ulating the adhesin synthesis) me-diate a significant portion of re-sponses to conditions required forbiofilm formation, since deletion ofPMT1, PMT4 or EFG1 genes pre-vented it. Transcriptomic analysisshows that Efg1p is also requiredfor the induction of the genes im-plicated in hypoxic conditions such


EC

M

Aspergillus fumigatus biofilm in vitro.The arrow indicates extracellular matrix(ECM) in the biofilm

Etafilcon A Galyfilcon A Lotrafilcon A Balafilcon A Alphafilcon A Polymacon A

C. a

lbic

ans

F. s

ola

ni

as the ones existing inside thebiofilm and in deep host tissues.

C. albicans as well as Fusariumform biofilms on all types of lensesbut the biofilm architecture variedwith the lens type and with thestrain as demonstrated with differ-ent Fusarium strains. The eradica-tion of the contaminants by contactlens care solutions is highly depen-dent on the type of solution used.Fusarium and C. albicans cells inbiofilms are resistant to severalsterilizing solutions conversely tothe planktonic state, suggesting apossible role for biofilms in the re-

cent outbreaks of fungal keratitis.Seeing the fungus as a separate

entity is a complete remote idea.Pathogenic fungi have to be stud-ied as populations since their be-haviour in vivo will be totally dif-ferent and their physiology will betotally depending on the extracel-lular matrix forming the biofilm inwhich these populations leave.

Mahmoud GhannoumAnne BeauvaisJean-Paul Latgé

Invasive Fungal Infections in the Intensive Care Chairs: J. Meis, L. Klingspor

The heterogenous populationof severely ill patients admit-

ted to an intensive care unit (ICU)shares a high susceptibility to noso-comial fungal infections. A sympo-sium entitled “Invasive fungal infec-tions in the intensive care” was or-ganised by ECMM at the IUMS2008 held in Istanbul last August.This symposium, chaired by JacquesMeis and Lena Klingspor, broacheddifferent topics: infections caused by

Candida and by filamentous fungi,risk factors and prophylaxis, andantifungal therapy. The ad interimresults of the ECMM survey ondeep-seated Candida infections inICU surgical patients were report-ed by Lena Klingspor, convenor ofthe Working Group.

An overview on yeast and mouldinfections in ICU patients was pre-sented by Anna Maria Tortoranoand Sevtap Arikan, respectively.


Congress report

apparent increase in cases of zy-gomycosis in the setting ofvoriconazole prophylaxis, a verytimely lecture entitled: Is voricona-zole a risk factor? (J. Parada).

The clinical presentation and di-agnosis of zygomycosis was cov-ered in session 3 with lectures onthe clincal presentation in adults(George Samonis), zygomycosis inneonates and children (EmmanuelRoilides), conventional methods ofdiagnosis (Cornelia Lass-Flörl),molecular methods of diagnosis(Eric Dannaoui), and susceptibilitytesting: in vitro – in vivo correla-tions (Juan Rodríguez Tudela).

The second days programmeconcluded with a session on treat-ment. The challenges in the man-agement of zygomycosis was pre-sented by George Daikos and L. Vrana. The use of liposomal am-photericin B (AmBisome) was re-viewed by Georgios Petrikkos.Oliver Cornely posed the question:posaconazole: an alternative or anadd-on-choice? Andreas Groll pre-sented the current thinking on theuse of hyperbaric oxygen and otheradjunctive methods of manage-ment and the session was conclud-

ed with a video presentation on thesurgical approach to treatment:perspectives from a maxillo-facialsurgeon (A. Rapidis). The final ses-sion was an interactive audienceand panel discussion on definitionsand proposals for formulating diag-nostic and clinical guidelines. Themeeting concluded with a meetingof the ECMM Working Group onZygomycosis. In summary, the IstInternational Forum on Zygomy-cosis was an excellent, exhaustivemeeting on an underrepresenteddisease area. The presentations ofthe symposium will be published asa collection of reviews in a forth-coming supplement of Clinical Mi-crobiology and Infection, facilitatedby additional welcomed supportfrom Gilead Sciences. The HellenicSociety for Medical Mycology andthe organising committee (G. Petrikkos, J. Meis, A. Mitrous-sia-Ziouva, E. Roilides, G. Samo-nis and A. Skiada) are to be con-gratulated on organising such a finemeeting. We look forward to simi-lar symposia in the future.

Malcolm Richardson


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Zygomycosis Chairs: G. Petrikkos, E. Tümbay

George Petrikkos (ΑthensUniversity, Greece) pre-

sented the current epidemiology ofzygomycosis in Europe, showingthe data from the ECMM WorkingGroup on Zygomycosis. Fifteencountries submitted 230 cases(Italy 60, Greece 36, Germany 35,Switzerland 22, France 21, Belgium16, Austria 12, Spain 9, Russia 6,Norway 5, Finland 2, Czech Re-public 2, Turkey 2, Netherlands 1and UK 1). Israel also submittedcases but they will be included in2008.

The mean age of the patientswas 50 years and 60% were male.The main underlying diseases werehematologic malignancies (45%),bone marrow transplantation(10%), trauma (17%), diabetes(9%), other malignancies (5%) andsolid organ transplantation (4%).The main sites of infection were thelung (29%), rhinocerebral (14%),the sinuses (13%), soft tissues(25%) and disseminated (15%).Statistical analysis showed correla-tion between hematological malig-nancy and pulmonary disease, aswell as between diabetes andrhinocerebral disease. Zygomyco-sis was proven in 114 cases andprobable in 116. Various methodsof diagnosis were used includinghistology, culture, direct mi-croscopy and molecular methods.The isolated fungi were mainlyRhizopus sp (24%), Mucor sp(22%) and Absidia sp (14%).

Mortality was 44.7%. On multi-variate analysis, the factors foundto be related to the outcome wereage, previous administration ofcaspofungin, trauma as an underly-ing factor, treatment with ampho-tericin B and surgical treatment.

The pathogenesis and host de-fenses against Zygomycetes wereanalyzed by Emmanuel Roilides(University of Thessaloniki,Greece). He pointed out that al-though the pathogenesis of zy-gomycosis has not been fully un-

derstood yet, many interesting as-pects of it have been studied, in-cluding the role of monocytes andneutrophils, various pro- and anti-inflammatory cytokines etc. Heconcluded that the genetic map-ping of important Zygomycetes willhelp unrevealing pathogenesis ofzygomycete infections and helpcreating more and better diagnosticand therapeutic targets.

Eric Dannaoui (Institut Pasteur,Paris, France) talked about con-ventional and molecular diagnosticmethods. He pointed out that mor-phological-based identification offungi can be erroneous in >20% ofcases. He presented data showingthat sequencing of ITS region is areliable method for accurate identi-fication of Zygomycetes and he alsotalked about the use of PCR testingon histology specimen.

Grit Walther (CBS Fungal Bio-diversity Center, Utrecht, TheNetherlands) presented the ongo-ing study of his group, the aim ofwhich is to achieve a reliable diag-nosis of mucormycosis by ITS bar-coding of the Mucorales. In orderto further cover the diversity of theMucorales species, the group is inthe process of generating ITS bar-codes for all species of the Muco-rales present in the CBS collection.These sequences will be used to setup a database for an accurate andrapid routine identification of Mu-corales species that will be madepublicly available through the CBSwebsite. This set of ITS DNA bar-code database will not only im-prove the reliability of the speciesrecognition, it will also facilitatethe detection of unknown patho-genic species and the search for apotential correlation betweenspecies and underlying diseases.

The pharmacology of antifungalagents against zygomycosis waspresented by Andreas Groll (Chil-dren's University Hospital, Muen-ster, Germany).

Livio Pagano (Università Cat-tolica del Sacro Cuore, Rome,Italy) talked about antifungal pro-phylaxis and therapy of zygomyco-sis. He talked about the traditionalapproach of treating the infectionwith amphotericin B, as well as the

emerging role of posaconazole. Healso presented in vitro studies,where the majority of Zygomycetesdemonstrated resistance to flu-conazole, itraconazole andechinocandins, whereas investiga-tional triazoles, such as posacona-zole were found to be active againstMucorales.

Summing up, this was a very in-teresting symposium on zygomyco-sis, covering many aspects of theserare infections, which have beenrising in recent years.

George L. Petrikkos

1st International Forum on ZygomycosisThe 1st International Forum

on Zygomycosis was orga-nized by the Hellenic Society forMedical Mycology under the aus-pices of the ECMM, and supportedby a generous unrestricted educa-tional grant from Gilead SciencesInternational. One of the mostspectacular Greek temples, TheTemple of Poseidon, is positionedon Cape Sounion so adding to theatmosphere of the conference.Some 98 faculty and participantsgathered to update each other andexchange new information of zy-gomycosis. The meeting was thefirst of its kind. The Forum-stylesymposium was designed to answerthe central question: is zygomycosisan emerging or re-emerging infec-tious disease, and what do we real-ly know about zygomycosis?

The content of the symposiumwent a long way in achieving thegoals of the meeting. Backgroundtopics covered what is known (nota lot!) about the environmentalsources of Zygomycetes (MalcolmRichardson) and a useful updateon the taxonomy of the agents ofzygomycosis (Elizabeth Johnson).The classification of the Zygomy-cota is in a state of flux so this pre-sentation was particularly timely.The remainder of the symposiumwas divided into a number of ses-sions.

Session 1 was devoted to recenttrends in the epidemiology of zy-gomycosis with talks on changingepidemiology (Jacques Meis), inci-dence of zygomycosis in transplantrecipients (M. Cuenca-Estrella),and hospital acquired zygomycosisillustrated by a recent outbrek inAthens (A. Antoniadou).

Session 2 explored risk factorsand pathogenesis. Lectures includ-ed zygomycosis related to trauma(Anna Skiada), deferrioxamine vs.Deferasirox: what is the role of iron(A. Symeonidis); zygomycosis andneutropenia (Livio Pagano), zy-gomycosis and diabetes (OlivierLortholary), and considering the

Zygomycosis (mucormycosis): anemerging or re-emerging disease?

Cape Sounion, south of Athens, Greece, 30th May – 1st June 2008Report on...

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perts from 24 European countriesand Australia, held in 2007, level A1evidence-based recommendationsfor antifungal prophylaxis in allo-geneic HSCT or inductionchemotherapy of acute leukemiawere made for posaconazole 200 mgtid oral or fluconazole 400 mg qdiv/oral.

Equivalent (A1) recommenda-tions for empirical treatment of fun-gal infection were made for liposo-mal amphotericin B 3mg/kg orcaspofungin 50mg. For first linetreatment of invasive pulmonary as-pergillosis, ECIL-2 made an A1 rec-ommendation for voriconazole 2 x 6mg/kg D1 then 2 x 4 mg/kg. No spe-cific treatment received an A1 rec-ommendation for salvage therapy,but posaconazole, caspofungin andvoriconazole all received BII recom-mendations.

The ECIL-2 recommendationsare broadly similar to those of theInfectious Diseases Society ofAmerica (IDSA), published earlierthis year, and discussed at theEBMT congress.

Cost effectiveness of antifungalprophylaxis

Putting key European and USrecommendations for antifungalprophylaxis into practice falls wellwithin internationally accepted cost-effectiveness thresholds, accordingto new data, presented by HelmutOstermann from the University ofMunich Hospital, Germany.

He calculated that, in Germany,it costs €21,073 to treat an invasivefungal infection, in terms of hospitalstay, diagnostic tests, blood prod-ucts, antifungal and other therapies.Against this background, heanalysed the cost per quality adjust-ed life year (QALY) of usingposaconazole for antifungal prophy-laxis, in line with the ECIL2 and ID-SA guidelines.

Taking account of all treatmentcosts and the impact of inductionchemotherapy and HSCT on qualityof life, Professor Ostermann showedthat the cost per QALY of usingposaconazole instead of the previousstandard treatment, itraconazole,was €8,342. This compares with the€30,000-€50,000 per QALY thresh-

old generally accepted by govern-ment health services for new thera-pies.

Professor Ostermann added thatsimilar analyses have been carriedout in a number of other countries,with cost savings calculated for usingposaconazole instead of itraconazolein the USA, Canada, Spain, Scot-land, the Netherlands, Switzerlandand France, and a cost per QALY of€1,173 in Belgium.

The Swiss experienceUsing clinical trial data for a cost-

effectiveness analysis of posacona-zole versus standard azole therapyfor the prevention of IFI in high-riskpatients in Switzerland, health econ-omist Roger-Axel Greiner and col-leagues reported a mean cost savingof CHF 1,118 in neutropenic pa-tients (CHF 9,089 vs 10,207)switched to posaconazole. In haema-tological patients with GVHD,switching to posaconazole was asso-ciated with a CHF 7041 increase incosts (CHF 17,720 vs 10,679). But, atCHF 48,324, the cost per life yearsaved fell below the CHF 60,000threshold accepted as cost effective.

The Spanish experienceIn another demonstration of the

impact of guidelines implementa-tion, Rafael Duarte, from the Hospi-tal Duran i Reynals, Barcelona,Spain, reported that switching fromitraconazole to posaconazole pro-phylaxis in allogeneic HSCT pa-tients reduced prophylaxis failureand improved fungal infection sur-vival, with a trend towards an im-provement in overall survival. Noneof 13 consecutive patients givenposaconazole prophylaxis sinceguidelines implementation in June2007 required additional antifungaltreatment for infection within 100days of their transplant, comparedwith 31% of 13 consecutive patientswho received itraconazole prophy-laxis before guidelines implementa-tion (p=0.04). Fungal infection-freesurvival was 85% at 100 days in theposaconazole group, compared to46% with itraconazole (p=0.03).Overall survival was 85% and 69%respectively (p=0.08).

Dr Duarte concluded that

posaconazole was well toleratedwith no significant toxicity, thoughhe drew attention to the need to re-duce the dose of cyclosporin A inpatients using this anti-rejectiondrug, because of its interaction withposaconazole.

Future directionsA key study aimed at determin-

ing which part of the DNA extrac-tion process needs to be improved inorder to make Aspergillus PCR test-ing more practicable is expected toget underway in the next fewmonths. Outlining the study, PeterDonnelly, from Radbourd Universi-ty Nijmegen Medical Centre in TheNetherlands, updated delegates onthe progress of the Aspergillus PCRWorking Group of the InternationalSociety for Human and Animal My-cology (ISHAM). He explained thatan initial review had concluded thatDNA extraction rather than the per-formance of the various PCR tech-niques is the main obstacle to wideruse. The extraction process willtherefore be explored at 24 centres,and the basic requirements for clini-cal validation have also been agreed.Professor Donnelly reported that itis hoped to propose a new standardfor PCR testing by early 2009.

Serial galactomannan resultscould prove a useful predictor of sur-vival in patients with IA, and testsshould be included in future treat-ment studies, concluded JohanMaertens, from the University Hos-pital Gasthuisberg, Leuven, Bel-gium. He presented data from tworecent studies showing that galac-tomannan index (GMI) correlateswell with survival. In the first study,in 56 adults with haematologic can-cer receiving antineoplastic therapy,there was a strong correlation be-tween survival outcome and GMI(p< 0.0001), and the results werecomparable for neutropenic andnon-neutropenic patients. A similarfinding has been reported in a sec-ond study of 43 patients. But datafrom larger numbers of patients arenow needed, said Dr Maertens.

Jenny Bryan


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ated with fewer deaths and less vari-ation between the two types oftransplant (57% and 44% respec-tively).

Data from a retrospective analy-sis of 306 patients undergoing HSCTfrom unrelated donors (60%), fami-ly mismatched (23%), mismatchedunrelated (11%) or cord blood(6%), presented by Anna MariaRaiola from San Martino Hospital,Genoa, Italy, confirmed the excessrisk of invasive aspergillosis (IA) inallogeneic transplants. In the study,37 patients had probable and 8 hadproven IA, with a prevalence of15%. The median time to onset was53 days after HSCT (range 4-449days), with infections roughly divid-ed between early and late onset.Mortality was 76%, with 67% relat-ed to IA, and IA the primary causein 40%. Late take of neutrophils andsteroid therapies were related to in-creased risk of IA, and ATG use inthe conditioning regimen, steroidtherapy, relapse, IgA andcholinesterase at diagnosis of IAwere all identified as predictors ofsurvival.

Dr Raiola concluded that IA isassociated with high mortality, espe-cially in patients whose immune sys-tem does not recover after HSCT.

Empirical versus pre-emptiveantifungal therapy?

Pre-emptive antifungal therapy isa cost-effective alternative to empir-ical therapy in patients who are neu-tropenic for relatively short periods(under 15 days), but further refine-ment of diagnostic techniques isneeded before it can be recommend-ed more widely for patients who arelikely to have a low neutrophil countfor more prolonged periods.

This was the conclusion ofCatherine Cordonnier, from theHôpital Henri Mondor, Paris,France, at the end of a presentation

during which 38% of the audiencesaid that they used pre-emptivetreatment in allogeneic HSCT pa-tients and 34% said they used theempirical approach.

Professor Cordonnier’s advicewas based on the results of the PRE-VERT study, which compared em-pirical and pre-emptive treatment in293 patients with haematologicalmalignancies and an expected peri-od of neutropenia of 10+ days dur-ing their treatment. All werescreened twice weekly for galac-tomannan antigen.

Seventeen patients in the studyhad an IFI, 4 (2%) in the empiricalgroup and 13 (9%) in those receiv-ing pre-emptive therapy (p<0.02),though the overall survival rate wascomparable (p=0.12). Further inves-tigation revealed that there was nodifference in infection rate betweenthe two treatment approaches whenneutropenia was short. But thelonger the period of neutropenia,the greater was the risk of infectionwith pre-emptive therapy.

Professor Cordonnier thereforerecommended that future pre-emp-tive strategies should include morerefined techniques - imaging toolsor biological markers - to increasediagnostic accuracy. She added thatpre-emptive treatment should beevaluated against prophylactic ap-proaches.

Guidelines updates At an EBMT Infectious Dis-

eases Working Party session held atthe congress, Professor Cordonnierintroduced the recently updatedEuropean Conference on Infectionin Leukaemia (ECIL-2) guidelines,which elaborated on the originalguidance on the prophylaxis andtreatment of infection complica-tions in leukaemia patients pro-duced in 2005.

At a consensus meeting of 52 ex-

34th Annual Meeting of the EBMTHaematopoietic stem cell trans-

plantation (HSCT) is widelyused in the treatment of blood and lym-phoid cancers, and a range of other im-mune diseases, with more than 30,000autologous and 15,000 allogeneic proce-dures performed annually worldwide.But, as some 5000 delegates at the recent34th Annual Meeting of the EuropeanGroup for Blood and Marrow Trans-plantation (EBMT) congress heard,success is hindered not only by a shortageof fully matched grafts, but by compli-cations such as invasive fungal infection(IFI) associated with the prolonged im-munosuppression that accompaniesHSCT.

High-risk groups for Aspergillus infection

IFI is six times more common inpatients undergoing HSCT thanthose who have autologous grafts,and the risk is also raised in patientswho have umbilical cord bloodtransplants, according to data pre-sented at the congress.

Livio Pagano, from the Policlini-co Gemelli, Rome, Italy, reportedan IFI rate of 3.8% in a retrospectivecohort study of transplant patientstreated at 11 Italian centres - 7.8% inthose undergoing allogeneic trans-plants, compared to 1.2% in thosewho had an autologous graft. As-pergillosis mortality was also higherin allogeneic than autologous trans-plant patients - 77% and 14% re-spectively - with candidaemia associ-

Report on...Florence, Italy,

30 March - 2 April 2008

Catherine Cordonnier

Announcements

Mycology newsletter - December 2008 35Mycology newsletter - December 200834

The 4th Congress onTrends in Medical

Mycology (TIMM-4) willbe held in Athens, Greecefrom the 18th till the 21stof October 2009. TIMMmycological internationalmeetings are jointly orga-nized by the EuropeanConfederation of MedicalMycology (ECMM) andby the Infectious DiseasesGroup of the EuropeanOrganization for Re-search and Treatment ofCancer (EORTC-IDG).TIMM have taken one ofthe most important places among the meetings in thefield of fungal infections globally, and has become a fo-rum in which investigators and clinicians from all overthe world exchange research results and opinions onmedical practice. Well-known speakers discuss themost important advances in basic science and clinicalresearch in mycology. The executive committee in col-laboration with the national and international scientificcommittees works hardly in order to prepare an excel-lent scientific program and make the participation tothe congress a long-lasting memory. The meeting is de-signed for infectious disease specialists, haematologists,oncologists, transplant physicians, microbiologists, im-munologists, dermatologists, intensivists and otherhealth workers with interest in medical mycology.

The preparation for the meeting is going very well.The program of the Congress has come close to final-ization and experts on the field are invited to give lec-tures on a variety of interesting laboratory and clinicaltopics within human mycology. Within its 3-day dura-tion the Congress will contain five high-quality plenarysessions discussing and updating hot issues in mycolo-gy. There will be sixteen workshops covering a broadspectrum of different mycological topics, four oral pre-sentation sessions where the most interesting abstractswill be presented and sessions of poster rounds andviewing. The poster sessions will encourage one-to-onediscussions between faculty, presenters and delegates.The Congress will also contain fifteen meet-the-expertsessions within which a selection of educational topicsbrought by the most expert mycologists will be pre-sented.

There will be two innovations in this meeting com-pared to the previous TIMM’s. First, in addition to thewell-established Drouhet Lecture that is given duringeach of the last several congresses, a new distinguished

lecture has been recentlyestablished and will be de-livered during TIMM-4for the first time. This isthe Ben de Pauw Lecturethat has been createdthrough an unrestrictedgrant by Gilead to theTIMM. Prof. Ben de Pauwhas been instrumental inthe creation and success ofthe EORTC-InfectiousDisease Group and it is agreat honor to have thefirst distinguished Ben dePauw Lecture delivered inAthens. A second innova-

tion in the Athens meeting is that more grants will begiven for the best abstracts and posters. This is expect-ed to attract more high-quality presentations to thecongress.

The venue for the TIMM-4 is in Athens, Greece.Athens is the most important classical city in Greece,the birthplace of democracy, science and philosophy.Athens is full of historical and cultural treasuresthroughout the downtown area and the surrounding re-gion. Acropolis with Parthenon, many other classicalmonuments and a number of beautiful Byzantinechurches as well as excellent museums make the visi-tors’ experience unforgettable. Greece will undoubted-ly give an irresistible background for this exciting sci-entific forum, providing not only a beautiful setting fora high powered meeting, but also a flavour of theGreek taste of life to all congress participants.

The meeting venue, Athens Hilton(www.athens.hilton.com), is located at the heart of theGreek capital, a few kilometers away from Acropolisand Athens historic town. Detailed information on theprogram will be published in January 2009 in the 2ndannouncement of the congress and on the congresswebsite www.timm2009.org. Abstract deadline is 1June 2009 and for more information contact the con-gress secretariat Congress Care [email protected]: 31-73-690-1415 or www.congresscare.com.

The TIMM-4 in Athens will once again offer excel-lent science and medicine in a superb venue. We lookforward to greeting you in Greece and discuss new de-velopments in medical mycology!

Emmanuel Roilides and George Petrikkoson behalf of TIMM-4 Executive Committee

Trends in Medical Mycology-4, Athens, October 2009

Announcements

ISHAM 2009: The 17th Congress in TokioISHAM has become one of the most active international

organizations in medical mycology, and its congress is anevent that you may not miss. The congress, held in Tokyo,25-29 May, 2009 is very reasonably priced: this is a greatchance to visit Japan! Registration for ISHAM2009 is nowopen. For accommodation, see online hotel online booking.There is a wide range of options between deluxe and budget.

The organizers have put together an excellent,

densely informative program covering all aspects ofmodern medical mycology. More than 50 symposiaand sessions are planned with distinguished speakerson themes in medical, veterinary and indoor mycolo-gy with a focus on human and animal health. Morethan 80 chairpersons have been confirmed for themajority of the Scientific Sessions and speaker selec-tion is progressing well; a list of chairpersons andspeakers will be available soon. The extremely widerange of experts will stimulate and expand the scopeof your research.

A significant amount of attention will be devoted toposters, so that all participants will have ample oppor-tunity to present their work. Every day there will beviewing as well as oral poster sessions in a poster fo-rum, held in addition to the regular poster exhibitions.Poster presenters in the PF will have 5 minutes of oralpresentation, may show 5 slides, and may receive 1question. Case reports are particularly welcome. In ad-dition, twelve poster prizes will be given to posters ofhighest quality.

The ISHAM congress will host a meeting forISHAM-affiliated organizations. The meeting is opento anyone volunteering to stimulate medical mycologyin all its aspects. Major theme is the promote network-ing and providing facilities for joint research. The agen-da is posted on the ISHAM website, www.ISHAM.org.

Each day several luncheon and evening seminarsare scheduled, and every evening a pleasant and inter-esting activity will be organized. Keynote lectures canbe found on the ISHAM website. In addition, severalISHAM Working Groups will hold their meetings.

Mycologists under 35 and having a great career inmind become ISHAM member and get their moneyback when participating ISHAM2009. Young memberspresent in Tokyo will receive an extra gift worth $ 100,-

Important dates:Call for Papers: On-line Abstract Submission for

Poster Presentations is open now.Abstract Submission Deadline: December 26, 2008.Early registration deadline at low fee: February 19,

2009.ISHAM 2009 is one of the top international con-

gresses, an optimum arena to present your latest re-search. Please join us in Tokyo and take advantage ofthis marvellous opportunity to enjoy intensive science,international contacts, and warm Japanese hospitality!

Hideoki Ogawa, Congress PresidentSybren de Hoog, ISHAM President

The program for the ISHAM congress in Tokyo 2009,http://www.congre.co.jp/isham2009/

Announcements

Mycology newsletter - December 2008 37Mycology newsletter - December 200836

The first meeting of the ISHAM Working Group onFilamentous fungi and chronic respiratory infec-

tions in cystic fibrosis will be organized in Angers Uni-versity, Angers, France, on 7 and 8 June, 2009. Aim isto focus attention on the much overlooked respiratoryinfections caused by filamentous fungi in patients withcystic fibrosis.

Beside bacteria which remain the major causativeagents of respiratory infections in the context of cysticfibrosis (CF), several filamentous fungi may also colo-nize the respiratory tract of these patients. This fungalcolonization of the airways, facilitated by the frequentand prolonged cures of antibiotics and by the use ofcorticosteroids, may also lead to true respiratory infec-tions whose frequency regularly increases along withthe development of lung transplantation and the in-crease in life expectancy. Apart from Aspergillus fumi-gatus, numerous other species are reported increasing-ly, such as Scedosporium apiospermum, A. terreus, Ex-ophiala dermatitidis and S. prolificans, some of thembeing poorly susceptible to current antifungals andtherefore difficult to treat. However, the prevalence ofthese fungi in the context of CF is certainly underesti-mated and their clinical significance still remains to bedefined. Large scale-multicenter studies should be de-

signed in order to define the real prevalence of thesespecies and the clinical significance of their recoveryfrom respiratory secretions, but also to highlight possi-ble geographic variations in their prevalence and to im-prove the biological diagnosis of airway coloniza-tion/infection. Additionally, numerous questions raisefrom the colonization of the airways by these filamen-tous fungi, and basic research on the ecology of thesefungi, their biochemistry, and their pathogenic mecha-nisms should be promoted to define prophylactic mea-sures or to develop more effective antifungal drugs.

The Workshop will be open to anyone who wishesto contribute to the study of chronic respiratory infec-tions caused by filamentous fungi in patients with CF. Itwill be asked to each attendant to give a short presen-tation of his or her lab and of the work(s) that has beendone in the past few years in our research field. Pre-sentation of scientific projects in this area with searchof partners is also encouraged. But a large part of thismeeting will also be dedicated to discussions in order toplan future developments and collaborative studies.The number of participants is limited to 50 and therewill be no fee.

Jean-Philippe Bouchara

Announcements

3rd Pan African Medical MycologySociety (PAMMS) ConferenceAbuja, Nigeria, February 25-27, 2009

Previous meetings

Ssuccessful 1st meeting (“Medical Mycology: The AfricanPerspective”) was held at the Hartenbos Beach Resort

near Mossel Bay in the Western Cape, South Africa on 25January 2005. The Pan African Medical Mycology Society(PAMMS) was inaugurated during this meeting and a steer-ing committee consisting of Hester Vismer (Cape Town,South Africa), Ifeoma Enweani (Ekpoma, Nigeria) and ElSheikh Mahgoub (Khartoum, Sudan) was elected to look af-ter PAMMS during its first few years.

The 2nd meeting was also held in CTICC, CapeTown, South Africa between May 6-8, 2007. Duringthis meeting PAMMS Council members were electedviz Hester Vismer (Cape Town) President, Ifeoma En-weani (Nnewi, Nigeria) Vice President, John Rheeder(South Africa) Secretary, Alf Botha (South Africa),Abdalla Ahmed (Saudi Arabia), and Ahmad Mohar-ram (Egypt) as members. Membership of the PAMMSis free, as the Africa Fund for Fungal Biodiversity andMycotic Infections, initiated by Sybren de Hoog andJacques Meis of the Netherlands, will cover the initialcosts of the Society.

Conference Announcement It is a pleasure to invite you to attend the 3rd meet-

ing of the PAMMS in Abuja to be held at the NationalCenter for Women Development (NCWD) located inthe Central Business District. The conference will pro-vide medical mycologists from Africa with a unique op-portunity to present their latest research findings, tofoster collaboration and to establish long-term rela-tions between scientists from Africa and abroad. APAMMS General Meeting will be held to discuss vari-ous updates on Medical Mycology Studies. Invitedspeakers from the African continent and speakers fromoutside Africa, working on topics concerning Africanfungi will participate in the meeting.

Poster presentations will also form an important

part of the programme. In addition to the stimulating scientific programme

planned for PAMMS 2009, Abuja is the current capitalof Nigeria and is situated at the heart of Nigeria. It hasa diverse culture with tourist attractions and hospitablepeople.

Organising Committee Ifeoma Enweani (Chairperson), Grace Ayanbimpe

(Treasurer), Members: Lyidia Abia-Bassey, EmekaNweze, Harish Gugnani, Afe Ekundayo, Dennis Ag-bonlahor, Francisca Okungbowa, Onyechere Allison.

Scientific Committee Hester Vismer (South Africa), David Katerere

(Cape Town), Jacques Meis (Netherlands), Sybren deHoog (Netherlands), El Sheikh Mahgoub (Sudan), Ab-dalla Ahmed (Saudi Arabia), Ifeoma Enweani (Nige-ria), John Rheeder (South Africa).

Important Contacts and AddressesAll information regarding the PAMMS 2009 confer-ence is also available at the following website:http://www.cbs.knaw.nl/meetings

Enquiries Ifeoma Enweani (Chairperson) PAMMS 2009 Department of Medical Laboratory Science Faculty of Health Sciences & Technology College of Health Sciences Nnamdi Azikwe University, Nnewi Campus P.M.B.5001,NNEWI Anambra State, NIGERIA. Tel: +234 (0)8037 743 790 / +234 (0)806 688 8116 /+234 (0)42314349 E-mail: [email protected];[email protected]

ISHAM Working Group on Filamentousfungi and chronic respiratory infections in cystic fibrosisAngers, June 7-8, 2009

The clear ch ice...Broad spectrum without compromising efficacy in Aspergillosis1,2 and Candidiasis1,3

Over 17 years of clinical experience in more than 500,000 patients4

Reduced toxicity through unique liposomal delivery of amphotericin B5

Breadth. Depth. Duration

ABBREVIATED PRESCRIBING INFORMATIONPresentation: A sterile lyophilised product for intravenous infusion.Each vial contains 50 mg of amphotericin B, encapsulated inliposomes. Indications: The treatment of severe systemic and/ordeep mycoses where toxicity (particularly nephrotoxicity) precludesthe use of conventional systemic amphotericin B in effective dosages.The empirical treatment of presumed fungal infections in febrileneutropenic patients, where the fever has failed to respond to broad-spectrum antibiotics and appropriate investigations have failed todefine a bacterial or viral cause.Dosage & Administration:Preparation – Follow the reconstitution instructions exactly as givenin the SmPC. Administration – AmBisome should be administered byintravenous infusion over a 30 – 60 minute period. Therecommended concentration for intravenous infusion is 0.2 mg/ml to2.0 mg/ml. Therapy for systemic and/or deep mycoses is usuallyinstituted at a daily dose of 1.0 mg/kg of body weight, andincreased stepwise to 3.0 mg/kg, as required. Data are presentlyinsufficient to define total dosage requirements and duration oftreatment necessary for resolution of mycoses. However, acumulative dose of 1.0 – 3.0 g of amphotericin B as AmBisome over3 – 4 weeks has been typical. Dosage of amphotericin B asAmBisome must be adjusted to the specific requirements of eachpatient. The recommended dose for empirical treatment in febrileneutropenia is 3 mg/kg body weight per day. Treatment should becontinued until the recorded temperature is normalised for 3consecutive days. In any event, treatment should be discontinuedafter a maximum of 42 days. Children have been successfully treatedwith AmBisome without reports of unusual adverse events and havereceived comparable doses to adults on a per kilogram body weightbasis. There are no specific dosage recommendations or precautionsfor elderly patients. Contra-Indications: Hypersensitivity to anyof the constituents of AmBisome, unless the condition requiringtreatment is life threatening and amenable only to AmBisometherapy. Warnings: Although anaphylactic or severe allergicreactions are rare, administration of a test dose is still advisable. Ifa small amount of AmBisome (e.g. 1 mg) can be administered forabout 10 minutes without severe allergic reactions within 30 minutes,the dose can be continued. Laboratory evaluation of renal, hepaticand haematopoietic function should be performed at least weeklyand particular attention should be given to patients receiving

concomitant therapy with nephrotoxic drugs. Levels of serumpotassium and magnesium should be monitored regularly. Use indiabetic patients: Each vial of AmBisome contains approximately900 mg of sucrose. Use in dialysis patients: Haemodialysis orperitoneal dialysis does not appear to affect the elimination ofAmBisome and data suggest no dose adjustment is required,however administration should be avoided during the haemodialysisprocedure. Use in pregnancy: As the safety of AmBisome inpregnancy has not been established, the risk/benefit ratio must beconsidered. Interactions: No specific pharmacokinetic interactionsof AmBisome with other drugs have been reported in clinical trialsto date; patients requiring concomitant drug therapy should bemonitored closely. Concurrent administration of other nephrotoxicagents may increase the risk of nephrotoxicity in some patients. Sideeffects: In two double-blind, comparative studies, AmBisometreated patients experienced a significantly lower incidence ofinfusion-related reactions, as compared to patients with eitherconventional amphotericin B or amphotericin B lipid-complex. Lessfrequent infusion-related reactions may include back pain and/orchest tightness or pain, dyspnoea, bronchospasm, flushing,tachycardia and hypotension, and these resolved rapidly withcessation of the infusion. In a double-blind study involving 687patients, nephrotoxicity with AmBisome was approximately half thatfor conventional amphotericin B. In another double-blind studyinvolving 244 patients, the incidence of nephrotoxicity withAmBisome was approximately half that for amphotericin B lipidcomplex. Additional adverse events observed in clinical trials includenausea, vomiting, hypokalaemia, creatinine and BUN increase,hypomagnesaemia, hypocalcaemia, hyperglycaemia, hyponatraemia,liver function test abnormalities, hyperbilirubinemia, vasodilation,increased alkaline phosphatase, diarrhoea, abdominal pain, rigors,headache, rash and pyrexia. Convulsion, thrombocytopenia,anaphylactoid reactions, hypersensitivity, angioneurotic oedema andrenal insufficiency/failure have been reported rarely.Overdosage: In clinical trials, repeated daily doses up to 15mg/kg in adults and 10 mg/kg in children have been given withoutreported dose-dependent toxicity. If overdosage occurs, stopadministration immediately and carefully monitor hepatic, renal andhaematopoietic function. Pharmaceutical Precautions: Do not storeabove 25˚C. Do NOT freeze. As AmBisome does not contain any

bacteriostatic agent, from a microbiological point of view, thereconstituted and diluted product should be used immediately. In-usestorage would not normally be longer than 24 hours at 2 - 8˚C,unless reconstitution and dilution has taken place in controlled andvalidated aseptic conditions. Chemical and physical stability hasbeen demonstrated for 24 hours at 25˚C ± 2 and 7 days at 2 - 8˚Cfor reconstituted product. Following dilution with 5% dextrose,chemical and physical stability have been shown for 24 - 48 hoursat 25˚C ± 2 and 4 - 7 days at 2 - 8˚C (dependent upon finalconcentration). DO NOT STORE partially used vials. DO NOTRECONSTITUTE AMBISOME WITH SALINE, OR MIX WITH OTHERDRUGS. Legal category: POM. Package Quantities:Cardboard carton of 10 vials each. NHS price – Carton of 10 vials,£966.90. Product Licence Number: PL 16807/0001. Fullprescribing information is available from the marketing authorisationholder: Gilead Sciences International Ltd, Granta Park, Abington,Cambridge CB21 6GT.

CONSULT THE SUMMARY OF PRODUCT CHARACTERISTICSBEFORE PRESCRIBING

Date of preparation: August 2006. AmBisome is a trademark.

References:1. AmBisome, Summary of Product Characteristics, 5 July 2007.2. Cornely O et al. Clin Infect Dis 2007; 44: 1289-97.3. Ringdén O et al. J Antimicrob Chemother 1991; 28(Suppl B):

73-82.4. Data on file. Gilead Sciences International – AMB0700007. 5. Boswell GW et al. J Clin Pharmacol 1998; 38: 583-592.

Date of preparation: January 2008.INT/AMB/0108/CM/15

mycology - ecmm.euecmm.eu/files/ecmm_01_2008_a3.pdf · journal: mikologia lekarska (medical...

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