Emergence of Azole-Resistant Invasive Aspergillosis in HSCT Recipients in Germany

J Antimicrob Chemother. 2015 May;70(5):1522-6. doi: 10.1093/jac/dku566. Epub 2015 Jan 27.

Abstract

Objectives: 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.

Keywords: Aspergillus fumigatus; azole resistance; haematopoietic stem cell transplant recipients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Amino Acid Substitution
  • Antifungal Agents / pharmacology*
  • Aspergillus fumigatus / classification
  • Aspergillus fumigatus / drug effects*
  • Aspergillus fumigatus / genetics
  • Aspergillus fumigatus / isolation & purification
  • Azoles / pharmacology*
  • Cytochrome P-450 Enzyme System / genetics
  • Drug Resistance, Fungal*
  • Female
  • Fungal Proteins / genetics
  • Genotype
  • Germany / epidemiology
  • Hematopoietic Stem Cell Transplantation / adverse effects*
  • Humans
  • Invasive Pulmonary Aspergillosis / epidemiology*
  • Male
  • Microbial Sensitivity Tests
  • Microsatellite Repeats
  • Middle Aged
  • Molecular Typing
  • Mutant Proteins / genetics
  • Mycological Typing Techniques
  • Sequence Analysis, DNA

Substances

  • Antifungal Agents
  • Azoles
  • Fungal Proteins
  • Mutant Proteins
  • Cytochrome P-450 Enzyme System
  • cytochrome P-450 CYP51A, Aspergillus