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We investigated the prevalence of azole resistance of Aspergillus fumigatus isolates in the Netherlands by screening clinical A. fumigatus isolates for azole resistance during 2013-2018. We analyzed azole-resistant isolates phenotypically by in vitro susceptibility testing and for the presence of resistance mutations in the Cyp51A gene. Over the 6-year period, 508 (11%) of 4,496 culture-positive patients harbored an azole-resistant isolate. Resistance frequency increased from 7.6% (95% CI 5.9%-9.8%) in 2013 (58/760 patients) to 14.7% (95% CI 12.3%-17.4%) in 2018 (112/764 patients) (p = 0.0001). TR 34 /L98H (69%) and TR 46 /Y121F/T289A (17%) accounted for 86% of Cyp51A mutations. However, the mean voriconazole MIC of TR 34 /L98H isolates decreased from 8 mg/L (2013) to 2 mg/L (2018), and the voriconazole-resistance frequency was 34% lower in 2018 than in 2013 (p = 0.0001). Our survey showed changing azole phenotypes in TR 34 /L98H isolates, which hampers the use of current PCR-based resistance tests.

Background: Increasing resistance of Aspergillus fumigatus to triazoles in high-risk populations is a concern. Its impact on mortality is not well understood, but rates from 50% to 100% have been reported., Objectives: To determine the prevalence of voriconazole-resistant A. fumigatus invasive aspergillosis (IA) and its associated mortality in a large multicentre cohort of haematology patients with culture-positive IA., Methods: We performed a multicentre retrospective study, in which outcomes of culture-positive haematology patients with proven/probable IA were analysed. Patients were stratified based on the voriconazole susceptibility of their isolates (EUCAST broth microdilution test). Mycological and clinical data were compared, along with survival at 6 and 12 weeks., Results: We identified 129 A. fumigatus culture-positive proven or probable IA cases; 103 were voriconazole susceptible (79.8%) and 26 were voriconazole resistant (20.2%). All but one resistant case harboured environment-associated resistance mutations in the cyp51A gene: TR34/L98H (13 cases) and TR46/Y121F/T289A (12 cases). Triazole monotherapy was started in 75.0% (97/129) of patients. Mortality at 6 and 12 weeks was higher in voriconazole-resistant cases in all patients (42.3% versus 28.2%, P = 0.20; and 57.7% versus 36.9%, P = 0.064) and in non-ICU patients (36.4% versus 21.6%, P = 0.16; and 54.4% versus 30.7%; P = 0.035), compared with susceptible ones. ICU patient mortality at 6 and 12 weeks was very high regardless of triazole susceptibility (75.0% versus 66.7%, P = 0.99; and 75.0% versus 73.3%, P = 0.99)., Conclusions: A very high prevalence of voriconazole resistance among culture-positive IA haematology patients was observed. The overall mortality at 12 weeks was significantly higher in non-ICU patients with voriconazole-resistant IA compared with voriconazole-susceptible IA., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Triazole resistance in Aspergillus fumigatus is widespread and threatens first-line triazole therapy in patients with Aspergillus diseases., Objectives: To give an overview of the microbiology, epidemiology and clinical significance of triazole resistance in aspergillosis., Sources: PubMed search for articles on resistance in Aspergillus species., Content: Triazoles are not mutagenic but select resistance when spontaneous mutations occur that are better able to proliferate in the triazole-containing environment. The major target for resistance mutations involves the Cyp51A gene, encoding an enzyme involved in cell wall synthesis. Triazole-resistance selection environments include patient treatment and organic matter containing triazole fungicide residues. Reported resistance frequencies vary widely between countries and hospitals, and resistance significantly complicates the diagnosis and treatment of Aspergillus diseases. Cultures may harbour various resistance phenotypes and multiple colonies must be analysed to detect resistance. PCR tests have become available for resistance detection in culture-negative patients, but show limited sensitivity. Individuals with triazole-resistant invasive aspergillosis have a 21% higher day-42 mortality compared with triazole-susceptible infection, and to prevent excess mortality resistant cases require first-line therapy that covers resistance. The recent ESCMID-ECMM-ERS Aspergillus guideline recommends resistance testing in A. fumigatus and local resistance surveillance. If resistance rates exceed 10% liposomal amphotericin B or triazole and echinocandin first-line therapy should be considered., Implications: Triazole resistance significantly complicates the management of aspergillosis and multidisciplinary research from a 'One-health' perspective is required to retain the triazole class for medical use., (Copyright © 2018 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)