Emerging azole-resistant Aspergillus fumigatus in haematological patients in the Netherlands

Daphne Scoop, Peter von dem Borne, Ed J. Kuijper, Martha van der Beek


Background: Recent reports show a steady increase of azole-resistant clinical and environmentalAspergillus fumigatus isolates with highest rates found in The Netherlands. The mortality of patientswith azole resistant invasive aspergillosis (IA) approaches 90%. Risk assessment for resistance of patients with IA is urgently needed to guide empirical treatment of invasive fungal disease. Therefore, we performed a retrospective study to determine the prevalence of azole resistance amonghematological patients with culture positive IA and collected patient data to identify risk factors for azole-resistance.

Material/methods: Using standardized questionnaires, clinical and microbiological data wereretrieved from the hospital patient information system on all hematological patients with culture proven invasive aspergillosis (IA) between January 2010 and July 2014 at a   tertiary care hospital in The Netherlands. The database of the department of Hematology was used to recognize patientsconsidered at risk for development of IA. Susceptibility of Aspergillus fumigatus to triazoles was tested by 4-well azole-agar screening. Suspected triazole-resistance was confirmed by phenotypical and genotypical testing at the Mycology Reference Laboratory in Nijmegen. Decreased susceptibility wasdefined based on EUCAST clinical breakpoints for azoles. Fisher's exact test and Mann-Whitney U test were used for univariate statistical analysis of risk factors and outcome parameters.

Results: Between January 2010 and July 2014, 570 adult hematological patients were considered at risk for IA. Of 570 patients, 36 (6,3%) patients developed culture positive IA with Aspergillus spp. A.fumigatus isolates of 10 of these 36 patients showed decreased susceptibility to triazoles (28%). Cyp51A-analysis of these isolates showed TR34/L98H in 7 cases, TR46/Y121F/T289A in 1 case and no known mutation in 2 cases. Comparison of patients with an azole-resistant isolate and patients withan azole-susceptible isolate showed no risk factor such as agricultural profession, rural site of residence, previous exposure to azoles either as prophylaxis or as treatment or inadequate serumlevels of anti-fungal prophylaxis. Crude mortality at 90 days was 80% in patients with azole-resistant isolates, compared to 54% in patients with azole-susceptible isolates (P=0,06).

Conclusions: The high incidence of 28% azole-resistant A.fumigatus in culture-positive IA found in hematological patients urges a reevaluation of empirical treatment, since no risk factor could be identified. The importance of an appropriate treatment is illustrated by the high mortality among patients with IA caused by azole-resistant A.fumigatus. 


abstract No: 

    • ECCMID 26th (2016)