R Seufert1,2, L Sedlacek3, B Kahl4, M Hogardt5, A Hamprecht6, G Haase7, F Gunzer8, A Haas9, S Grauling-Halama10,11, C R MacKenzie12, A Essig13, F Stehling14, S Sutharsan15, S Dittmer1, D Killengray1, D Schmidt1, N Eskandarian1, E Steinmann16,17, J Buer1, F Hagen18,19, J F Meis18,20,21, P-M Rath1, J Steinmann1,2. 1. Institute of Medical Microbiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. 2. Institute of Clinical Hygiene, Medical Microbiology and Infectiology, Paracelsus Medical University, Nuremberg, Germany. 3. Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany. 4. Institute of Medical Microbiology, University Clinics Münster, Münster, Germany. 5. Institute of Medical Microbiology and Infection Control, University Hospital Frankfurt, Frankfurt am Main, Germany. 6. Institute for Medical Microbiology, Immunology and Hygiene, University Hospital of Cologne, Cologne, Germany. 7. Clinical Laboratory and Diagnostic Services (LDZ), Rheinisch-Westfälische Technische Hochschule Aachen University Hospital, Aachen, Germany. 8. Institute of Medical Microbiology and Hygiene, Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany. 9. Max von Pettenkofer-Institute of Hygiene and Medical Microbiology, Ludwig-Maximilians-University Hospital, Munich, Germany. 10. Department of Infectious Diseases, Medical Microbiology and Hygiene, Ruprecht-Karls University Heidelberg, Heidelberg, Germany. 11. Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany. 12. Institute of Medical Microbiology and Hospital Hygiene, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany. 13. Institute of Medical Microbiology and Hygiene, Ulm University Hospital, Ulm, Germany. 14. Department of Pediatric Pulmonology and Sleep Medicine, University of Duisburg-Essen, Children's Hospital, Essen, Germany. 15. Department of Pneumology, Ruhrlandklinik, West German Lung Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany. 16. Institute for Experimental Virology, TWINCORE Centre for Experimental and Clinical Infection Research [a joint venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI)], Hannover, Germany. 17. Department of Molecular and Medical Virology, Ruhr-University Bochum, Bochum, Germany. 18. Department of Medical Microbiology and Infectious Diseases, Canisius Wilhelmina Hospital, Nijmegen, The Netherlands. 19. Department of Medical Mycology, Westerdijk Fungal Biodiversity Institute, Utrecht, The Netherlands. 20. Centre of Expertise in Mycology, Radboud University Medical Centre/Canisius Wilhelmina Hospital, Nijmegen, The Netherlands. 21. Department of Medical Microbiology, Radboud University Medical Centre, Nijmegen, The Netherlands.
Abstract
Objectives: Aspergillus fumigatus is the most prevalent filamentous fungus in the respiratory tract of patients with cystic fibrosis (CF). The aim of this prospective multicentre study was to investigate the prevalence of azole-resistant A. fumigatus (ARAF) in respiratory secretions from CF patients across Germany and to characterize ARAF isolates by phenotypic and molecular methods. Methods: Twelve tertiary care centres from Germany participated in the study. In total, 2888 A. fumigatus isolates from 961 CF patients were screened for ARAF by using azole-containing agar plates. Antifungal susceptibility testing of isolates was performed by broth microdilution according to EUCAST guidelines. Analysis of mutations mediating resistance was performed using PCR and sequencing of the cyp51A gene. Furthermore, genotyping by microsatellite PCR was performed. Results: Of a total of 2888 A. fumigatus isolates, 101 isolates from 51 CF patients were found to be azole resistant (prevalence per patient 5.3%). The Essen centre had the highest prevalence (9.1%) followed by Munich (7.8%), Münster (6.0%) and Hannover (5.2%). Most ARAF isolates (n = 89) carried the TR34/L98H mutation followed by eight G54E/R, one TR46/Y121F/T289A and one F219S mutation. In two isolates no mutation was found. Genotyping results showed no major clustering. Forty-five percent of CF patients with ARAF had previously received azole therapy. Conclusions: This is the first multicentre study analysing the prevalence of ARAF isolates in German CF patients. Because of a resistance rate of up to 9%, susceptibility testing of A. fumigatus isolates from CF patients receiving antifungal treatment should be part of standard diagnostic work-up.
Objectives:Aspergillus fumigatus is the most prevalent filamentous fungus in the respiratory tract of patients with cystic fibrosis (CF). The aim of this prospective multicentre study was to investigate the prevalence of azole-resistant A. fumigatus (ARAF) in respiratory secretions from CFpatients across Germany and to characterize ARAF isolates by phenotypic and molecular methods. Methods: Twelve tertiary care centres from Germany participated in the study. In total, 2888 A. fumigatus isolates from 961 CFpatients were screened for ARAF by using azole-containing agar plates. Antifungal susceptibility testing of isolates was performed by broth microdilution according to EUCAST guidelines. Analysis of mutations mediating resistance was performed using PCR and sequencing of the cyp51A gene. Furthermore, genotyping by microsatellite PCR was performed. Results: Of a total of 2888 A. fumigatus isolates, 101 isolates from 51 CFpatients were found to be azole resistant (prevalence per patient 5.3%). The Essen centre had the highest prevalence (9.1%) followed by Munich (7.8%), Münster (6.0%) and Hannover (5.2%). Most ARAF isolates (n = 89) carried the TR34/L98H mutation followed by eight G54E/R, one TR46/Y121F/T289A and one F219S mutation. In two isolates no mutation was found. Genotyping results showed no major clustering. Forty-five percent of CFpatients with ARAF had previously received azole therapy. Conclusions: This is the first multicentre study analysing the prevalence of ARAF isolates in German CFpatients. Because of a resistance rate of up to 9%, susceptibility testing of A. fumigatus isolates from CFpatients receiving antifungal treatment should be part of standard diagnostic work-up.
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