title: Emergence of azole-resistant invasive aspergillosis in HSCT recipients in Germany.
abstract: OBJECTIVE
  Aspergillus fumigatus is the most common agent of invasive aspergillosis (IA). In recent years, resistance to triazoles, the mainstay of IA therapy, has emerged in different countries worldwide. IA caused by azole-resistant A. fumigatus (ARAF) shows an exceedingly high mortality. In this study, IA due to ARAF isolates in HSCT recipients in Germany was investigated.
  
  
  METHODS
  The epidemiology of azole resistance in IA was analysed in two German haematology departments. Between 2012 and 2013, 762 patients received HSCT in Essen (n = 388) and Cologne (n = 374). Susceptibility testing of A. fumigatus isolates was performed by Etest, followed by EUCAST broth microdilution testing if elevated MICs were recorded. In all ARAF isolates the cyp51A gene was sequenced and the genotype was determined by microsatellite typing using nine short tandem repeats.
  
  
  RESULTS
  In total, A. fumigatus was recovered from 27 HSCT recipients. Eight patients had azole-resistant IA after HSCT, and seven of the cases were fatal (88%). All except one patient received antifungal prophylaxis (in five cases triazoles). TR34/L98H was the most common mutation (n = 5), followed by TR46/Y121F/T289A (n = 2). In one resistant isolate no cyp51A mutation was detected. Genotyping revealed genetic diversity within the German ARAF isolates and no clustering with resistant isolates from the Netherlands, India and France.
  
  
  CONCLUSIONS
  This report highlights the emergence of azole-resistant IA with TR34/L98H and TR46/Y121F/T289A mutations in HSCT patients in Germany and underscores the need for systematic antifungal susceptibility testing of A. fumigatus.
authors: Institute of Medical Microbiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany joerg.steinmann@uk-essen.de.
authors: J
authors: J
authors: Steinmann
authors: Institute for Medical Microbiology, Immunology and Hygiene, University Hospital of Cologne, Cologne, Germany.
authors: A
authors: A
authors: Hamprecht
authors: First Department of Internal Medicine, University of Cologne, Cologne, Germany German Centre for Infection Research (DZIF), Partner site Bonn-Cologne, Germany.
authors: M J G T
authors: MJ
authors: Vehreschild
authors: First Department of Internal Medicine, University of Cologne, Cologne, Germany German Centre for Infection Research (DZIF), Partner site Bonn-Cologne, Germany Clinical Trials Centre Cologne, ZKS Köln, BMBF 01KN1106, Center for Integrated Oncology CIO Köln Bonn, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
authors: O A
authors: OA
authors: Cornely
authors: 3rd Department of Internal Medicine, Mannheim University Hospital, University of Heidelberg, Mannheim, Germany.
authors: D
authors: D
authors: Buchheidt
authors: 3rd Department of Internal Medicine, Mannheim University Hospital, University of Heidelberg, Mannheim, Germany.
authors: B
authors: B
authors: Spiess
authors: Department of Bone Marrow Transplantation (AHE), West German Cancer Center, University Hospital Essen, Essen, Germany.
authors: M
authors: M
authors: Koldehoff
authors: Institute of Medical Microbiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors: J
authors: J
authors: Buer
authors: Department of Medical Microbiology and Infectious Diseases, Canisius Wilhelmina Hospital, Nijmegen, The Netherlands Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors: J F
authors: JF
authors: Meis
authors: Institute of Medical Microbiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors: P-M
authors: PM
authors: Rath
mesh_terms: D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution; D000935:Antifungal Agents / Q000494:pharmacology*; D001232:Aspergillus fumigatus / Q000145:classification / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D001393:Azoles / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D025141:Drug Resistance, Fungal; D005260:Female; D005656:Fungal Proteins / Q000235:genetics; D005838:Genotype; D005858:Germany / Q000453:epidemiology; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006801:Humans; D055744:Invasive Pulmonary Aspergillosis / Q000453:epidemiology*; D008297:Male; D008826:Microbial Sensitivity Tests; D018895:Microsatellite Repeats; D008875:Middle Aged; D058889:Molecular Typing; D050505:Mutant Proteins / Q000235:genetics; D016533:Mycological Typing Techniques; D017422:Sequence Analysis, DNA
chemical_list: D000935:Antifungal Agents; D001393:Azoles; D005656:Fungal Proteins; D050505:Mutant Proteins; D003577:Cytochrome P-450 Enzyme System; C465526:cytochrome P-450 CYP51A, Aspergillus
keywords: Aspergillus fumigatus; azole resistance; haematopoietic stem cell transplant recipients