Objectives: Invasive mold infections associated with Aspergillus species are a significant cause of mortality in immunocompromised patients. The most frequently occurring aetiological pathogens are members of the Aspergillus section Fumigati followed by members of the section Terrei. The frequency of Aspergillus terreus and related (cryptic) species in clinical specimens, as well as the percentage of azole-resistant strains remains to be studied. Methods: A global set (n = 498) of A. terreus and phenotypically related isolates was molecularly identified (beta-tubulin), tested for antifungal susceptibility against posaconazole, voriconazole, and itraconazole, and resistant phenotypes were correlated with point mutations in the cyp51A gene. Results: The majority of isolates was identified as A. terreus (86.8%), followed by A. citrinoterreus (8.4%), A. hortai (2.6%), A. alabamensis (1.6%), A. neoafricanus (0.2%), and A. floccosus (0.2%). One isolate failed to match a known Aspergillus sp., but was found most closely related to A. alabamensis. According to EUCAST clinical breakpoints azole resistance was detected in 5.4% of all tested isolates, 6.2% of A. terreus sensu stricto (s.s.) were posaconazole-resistant. Posaconazole resistance differed geographically and ranged from 0% in the Czech Republic, Greece, and Turkey to 13.7% in Germany. In contrast, azole resistance among cryptic species was rare 2 out of 66 isolates and was observed only in one A. citrinoterreus and one A. alabamensis isolate. The most affected amino acid position of the Cyp51A gene correlating with the posaconazole resistant phenotype was M217, which was found in the variation M217T and M217V. Conclusions:Aspergillus terreus was most prevalent, followed by A. citrinoterreus. Posaconazole was the most potent drug against A. terreus, but 5.4% of A. terreus sensu stricto showed resistance against this azole. In Austria, Germany, and the United Kingdom posaconazole-resistance in all A. terreus isolates was higher than 10%, resistance against voriconazole was rare and absent for itraconazole.

A O U Policlinico Vittorio Emanuele Catania Biometec University of Catania Catania Italy

Clinical Microbiology Laboratory National Kapodistrian University of Athens ATTIKON University Hospital Athens Athens Greece

Clinical Microbiology Puerta del Mar University Hospital University of Cádiz Cádiz Spain

Department 1 for Internal Medicine University Hospital of Cologne Cologne Germany

Department 1 for Internal Medicine University Hospital of Cologne Cologne Germany German Centre for Infection Research Partner Site Bonn Cologne Cologne Germany

Department 1 of Internal Medicine Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases Clinical Trials Centre Cologne Center for Integrated Oncology German Centre for Infection Research University of Cologne Cologne Germany

Department Applied and Industrial Mycology Westerdijk Fungal Biodiversity Institute Utrecht Netherlands

Department of Biomedical and Biotechnological Sciences University of Catania Catania Italy

Department of Biomedical Sciences for Health Università degli Studi di Milano Milan Italy

Department of Clinical Microbiology and Immunology Sackler School of Medicine Tel Aviv University Tel Aviv Israel

Department of Clinical Mycology Allergy and Immunology North Western State Medical University Saint Petersburg Russia

Department of Dermatology Hospital Ernest Lluch Martin Zaragoza Spain

Department of Hygiene and Medical Microbiology Klinikum Wels Grieskirchen Wels Austria

Department of Infectious Diseases and Clinical Microbiology Hacettepe University Medical School Ankara Turkey

Department of Laboratory Medicine Karolinska Institutet Karolinska University Hospital Stockholm Sweden

Department of Medical Microbiology and Infectious Diseases Canisius Wilhelmina Hospital Nijmegen Netherlands

Department of Medical Microbiology Hacettepe University Medical School Ankara Turkey

Department of Medical Mycology and Parasitology Invasive Fungi Research Center Mazandaran University of Medical Sciences Sari Iran

Department of Medical Mycology and Parasitology School of Medicine Iran University of Medical Science Tehran Iran

Department of Medical Mycology Vallabhbhai Patel Chest Institute University of Delhi New Delhi India

Department of Microbiology and Immunology KU Leuven Leuven Belgium

Department of Microbiology Faculty of Medicine and Dentistry Palacky University Olomouc and University Hospital Olomouc Olomouc Czechia

Department of Public Health and Pediatrics Microbiology Division Turin Italy

Departmento de Micología Instituto de Medicina Regional Universidad Nacional del Nordeste CONICET Resistencia Argentina

Division of Clinical Microbiology Department of Laboratory Medicine Medical University of Vienna Vienna Austria

Division of Clinical Mycology Department of Microbiology Vall d'Hebron University Hospital Barcelona Spain

Division of Hygiene and Medical Microbiology Medical University of Innsbruck Innsbruck Austria

Division of Mycology Department of Medial Microbiology Postgraduate Institute of Medical Education and Research Chandigarh India

Escola Paulista de Medicina Federal University of São Paulo São Paulo Brazil

Infectious Diseases Research Laboratory 4th Department of Internal Medicine ATTIKON University Hospital National and Kapodistrian University of Athens Athens Greece

Infectious Diseases Unit 3rd Department of Pediatrics Faculty of Medicine Aristotle University School of Health Sciences Hippokration General Hospital Thessaloniki Greece

Infectious Diseases Unit Department of Medical and Surgical Sciences S Orsola Malpighi University of Bologna Bologna Italy

Institute for Medical Microbiology Immunology and Hygiene University of Cologne Cologne Germany

Institute of Hygiene Microbiology and Environmental Medicine Medical University of Graz Graz Austria

Institute of Medical Microbiology University Hospital Essen University of Duisburg Essen Essen Germany

Laboratorio Centrale di Analisi Chimico Cliniche e Microbiologia IRCCS Foundation Cà Granda Ospedale Maggiore Policlinico Milan Italy

Microbiologia Hospital Universitario Miguel Servet IIS Aragon Universidad de Zaragoza Zaragoza Spain

Microbiology Division Department of Laboratory Medicine and Pathology Hamad Medical Corporation Doha Qatar

Microbiology Institute ASST Papa Giovanni XXIII Bergamo Italy

Mycology Reference Laboratory Public Health England Bristol United Kingdom

National Centre for Microbiology Instituto de Salud Carlos 3 Madrid Spain

National Reference Medical Mycology Laboratory Faculty of Medicine Institute of Microbiology and Immunology University of Belgrade Belgrade Serbia

School of Medicine European University Cyprus Nicosia Cyprus

Servei de Microbiologia Hospital de la Santa Creu 1 Sant Pau Barcelona Spain

Unit of Mycology Department of Clinical Microbiology Statens Serum Institute Copenhagen University Rigshospitalet Copenhagen Denmark

Unità Operativa Complessa di Microbiologia e Virologia Dipartimento di Patologia e Diagnostica Azienda Ospedaliera Universitaria Integrata Verona Italy

University of Texas MD Anderson Cancer Center Houston TX United States

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$a Zoran, Tamara $u Division of Hygiene and Medical Microbiology, Medical University of Innsbruck, Innsbruck, Austria.

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$a Azole-Resistance in Aspergillus terreus and Related Species: An Emerging Problem or a Rare Phenomenon / $c T. Zoran, B. Sartori, L. Sappl, M. Aigner, F. Sánchez-Reus, A. Rezusta, A. Chowdhary, SJ. Taj-Aldeen, MC. Arendrup, S. Oliveri, DP. Kontoyiannis, A. Alastruey-Izquierdo, K. Lagrou, GL. Cascio, JF. Meis, W. Buzina, C. Farina, M. Drogari-Apiranthitou, A. Grancini, AM. Tortorano, B. Willinger, A. Hamprecht, E. Johnson, L. Klingspor, V. Arsic-Arsenijevic, OA. Cornely, J. Meletiadis, W. Prammer, V. Tullio, JJ. Vehreschild, L. Trovato, RE. Lewis, E. Segal, PM. Rath, P. Hamal, M. Rodriguez-Iglesias, E. Roilides, S. Arikan-Akdagli, A. Chakrabarti, AL. Colombo, MS. Fernández, MT. Martin-Gomez, H. Badali, G. Petrikkos, N. Klimko, SM. Heimann, O. Uzun, M. Roudbary, S. de la Fuente, J. Houbraken, B. Risslegger, C. Lass-Flörl, M. Lackner,

520    9_

$a Objectives: Invasive mold infections associated with Aspergillus species are a significant cause of mortality in immunocompromised patients. The most frequently occurring aetiological pathogens are members of the Aspergillus section Fumigati followed by members of the section Terrei. The frequency of Aspergillus terreus and related (cryptic) species in clinical specimens, as well as the percentage of azole-resistant strains remains to be studied. Methods: A global set (n = 498) of A. terreus and phenotypically related isolates was molecularly identified (beta-tubulin), tested for antifungal susceptibility against posaconazole, voriconazole, and itraconazole, and resistant phenotypes were correlated with point mutations in the cyp51A gene. Results: The majority of isolates was identified as A. terreus (86.8%), followed by A. citrinoterreus (8.4%), A. hortai (2.6%), A. alabamensis (1.6%), A. neoafricanus (0.2%), and A. floccosus (0.2%). One isolate failed to match a known Aspergillus sp., but was found most closely related to A. alabamensis. According to EUCAST clinical breakpoints azole resistance was detected in 5.4% of all tested isolates, 6.2% of A. terreus sensu stricto (s.s.) were posaconazole-resistant. Posaconazole resistance differed geographically and ranged from 0% in the Czech Republic, Greece, and Turkey to 13.7% in Germany. In contrast, azole resistance among cryptic species was rare 2 out of 66 isolates and was observed only in one A. citrinoterreus and one A. alabamensis isolate. The most affected amino acid position of the Cyp51A gene correlating with the posaconazole resistant phenotype was M217, which was found in the variation M217T and M217V. Conclusions:Aspergillus terreus was most prevalent, followed by A. citrinoterreus. Posaconazole was the most potent drug against A. terreus, but 5.4% of A. terreus sensu stricto showed resistance against this azole. In Austria, Germany, and the United Kingdom posaconazole-resistance in all A. terreus isolates was higher than 10%, resistance against voriconazole was rare and absent for itraconazole.

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$a Sartori, Bettina $u Division of Hygiene and Medical Microbiology, Medical University of Innsbruck, Innsbruck, Austria.

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$a Sappl, Laura $u Division of Hygiene and Medical Microbiology, Medical University of Innsbruck, Innsbruck, Austria.

700    1_

$a Aigner, Maria $u Division of Hygiene and Medical Microbiology, Medical University of Innsbruck, Innsbruck, Austria.

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$a Sánchez-Reus, Ferran $u Servei de Microbiologia, Hospital de la Santa Creu I Sant Pau, Barcelona, Spain.

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$a Rezusta, Antonio $u Microbiologia, Hospital Universitario Miguel Servet, IIS Aragon, Universidad de Zaragoza, Zaragoza, Spain.

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$a Chowdhary, Anuradha $u Department of Medical Mycology, Vallabhbhai Patel Chest Institute, University of Delhi, New Delhi, India.

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$a Taj-Aldeen, Saad J $u Microbiology Division, Department of Laboratory Medicine and Pathology, Hamad Medical Corporation, Doha, Qatar.

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$a Arendrup, Maiken C $u Unit of Mycology, Department of Clinical Microbiology, Statens Serum Institute, Copenhagen University, Rigshospitalet, Copenhagen, Denmark.

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$a Oliveri, Salvatore $u Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy.

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$a Kontoyiannis, Dimitrios P $u University of Texas MD Anderson Cancer Center, Houston, TX, United States.

700    1_

$a Alastruey-Izquierdo, Ana $u National Centre for Microbiology, Instituto de Salud Carlos III, Madrid, Spain.

700    1_

$a Lagrou, Katrien $u Department of Microbiology and Immunology, KU Leuven, Leuven, Belgium.

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$a Cascio, Giuliana Lo $u Unità Operativa Complessa di Microbiologia e Virologia, Dipartimento di Patologia e Diagnostica, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.

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$a Meis, Jacques F $u Department of Medical Microbiology and Infectious Diseases, Canisius Wilhelmina Hospital, Nijmegen, Netherlands.

700    1_

$a Buzina, Walter $u Institute of Hygiene, Microbiology and Environmental Medicine, Medical University of Graz, Graz, Austria.

700    1_

$a Farina, Claudio $u Microbiology Institute, ASST Papa Giovanni XXIII, Bergamo, Italy.

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$a Drogari-Apiranthitou, Miranda $u Infectious Diseases Research Laboratory, 4th Department of Internal Medicine, ATTIKON University Hospital, National and Kapodistrian University of Athens, Athens, Greece.

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$a Grancini, Anna $u Laboratorio Centrale di Analisi Chimico Cliniche e Microbiologia, IRCCS Foundation, Cà Granda Ospedale Maggiore Policlinico, Milan, Italy.

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$a Tortorano, Anna M $u Department of Biomedical Sciences for Health, Università degli Studi di Milano, Milan, Italy.

700    1_

$a Willinger, Birgit $u Division of Clinical Microbiology, Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.

700    1_

$a Hamprecht, Axel $u Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Cologne, Germany.

700    1_

$a Johnson, Elizabeth $u Mycology Reference Laboratory, Public Health England, Bristol, United Kingdom.

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$a Klingspor, Lena $u Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.

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$a Arsic-Arsenijevic, Valentina $u National Reference Medical Mycology Laboratory, Faculty of Medicine, Institute of Microbiology and Immunology, University of Belgrade, Belgrade, Serbia.

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$a Cornely, Oliver A $u Department I of Internal Medicine, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, Clinical Trials Centre Cologne, Center for Integrated Oncology (CIO Köln-Bonn), German Centre for Infection Research, University of Cologne, Cologne, Germany.

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$a Meletiadis, Joseph $u Clinical Microbiology Laboratory, National Kapodistrian University of Athens, ATTIKON University Hospital Athens, Athens, Greece.

700    1_

$a Prammer, Wolfgang $u Department of Hygiene and Medical Microbiology, Klinikum Wels-Grieskirchen, Wels, Austria.

700    1_

$a Tullio, Vivian $u Department of Public Health and Pediatrics, Microbiology Division, Turin, Italy.

700    1_

$a Vehreschild, Jörg-Janne $u Department I for Internal Medicine, University Hospital of Cologne, Cologne, Germany. German Centre for Infection Research, Partner Site Bonn-Cologne, Cologne, Germany.

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$a Trovato, Laura $u A.O.U. Policlinico Vittorio Emanuele Catania, Biometec-University of Catania, Catania, Italy.

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$a Lewis, Russell E $u Infectious Diseases Unit, Department of Medical and Surgical Sciences, S. Orsola-Malpighi, University of Bologna, Bologna, Italy.

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$a Segal, Esther $u Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.

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$a Rath, Peter-Michael $u Institute of Medical Microbiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.

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$a Rodriguez-Iglesias, Manuel $u Clinical Microbiology, Puerta del Mar University Hospital, University of Cádiz, Cádiz, Spain.

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$a Roilides, Emmanuel $u Infectious Diseases Unit, 3rd Department of Pediatrics, Faculty of Medicine, Aristotle University School of Health Sciences, Hippokration General Hospital, Thessaloniki, Greece.

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$a Arikan-Akdagli, Sevtap $u Department of Medical Microbiology, Hacettepe University Medical School, Ankara, Turkey.

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$a Chakrabarti, Arunaloke $u Division of Mycology, Department of Medial Microbiology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.

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$a Colombo, Arnaldo L $u Escola Paulista de Medicina, Federal University of São Paulo, São Paulo, Brazil.

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$a Fernández, Mariana S $u Departmento de Micología, Instituto de Medicina Regional, Universidad Nacional del Nordeste, CONICET, Resistencia, Argentina.

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$a Martin-Gomez, M Teresa $u Division of Clinical Mycology, Department of Microbiology, Vall d'Hebron University Hospital, Barcelona, Spain.

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$a Badali, Hamid $u Department of Medical Mycology and Parasitology, Invasive Fungi Research Center, Mazandaran University of Medical Sciences, Sari, Iran.

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$a Petrikkos, Georgios $u School of Medicine, European University Cyprus, Nicosia, Cyprus.

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700    1_

$a Houbraken, Jos $u Department Applied and Industrial Mycology, Westerdijk Fungal Biodiversity Institute, Utrecht, Netherlands.

700    1_

$a Risslegger, Brigitte $u Division of Hygiene and Medical Microbiology, Medical University of Innsbruck, Innsbruck, Austria.

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$a Lass-Flörl, Cornelia $u Division of Hygiene and Medical Microbiology, Medical University of Innsbruck, Innsbruck, Austria.

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$a Lackner, Michaela $u Division of Hygiene and Medical Microbiology, Medical University of Innsbruck, Innsbruck, Austria.

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