Paradoxal Trends in Azole-Resistant Aspergillus fumigatus in a National Multicenter Surveillance Program, the Netherlands, 2013-2018.

Pieter P.A Lestrade,Karin Van Dijk,Bart J.A Rijnders,Sabine C De Greeff,Jaap Van Dissel,Greetje A Kampinga,Jochem B Buil,Alieke G Vonk,Martha T Van Der Beek,Jacques F Meis,Paul E Verweij,Annelot F Schoffelen,Willem J.G Melchers,Ed J Kuijper

doi:10.3201/eid2607.200088

Abstract

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). TR34/L98H (69%) and TR46/Y121F/T289A (17%) accounted for 86% of Cyp51A mutations. However, the mean voriconazole MIC of TR34/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 TR34/L98H isolates, which hampers the use of current PCR-based resistance tests.

Highlights

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
Our resistance surveillance showed an increasing frequency of azole resistance in clinical A. fumigatus isolates during 2013–2018 in the Netherlands
The resistance frequency varied between the 5 University Medical Centers (UMCs), the increasing trend was observed in all centers

Summary

Introduction

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. Triazoles with activity against aspergilli include itraconazole, voriconazole, posaconazole, and isavuconazole Use of this drug class has been threatened by the emergence of azole resistance, which was first reported in 1997 [5]. A recent cohort study showed that voriconazole resistance resulted in 21% lower day-42 survival in patients with culture-positive invasive aspergillosis compared with voriconazole-susceptible infection, indicating a major effect of resistance on patient survival [8]. Reports on azole resistance in the Netherlands prompted the national Center for Infectious Disease Control (Cib) to support a reference laboratory to set up a surveillance network to monitor trends in azole-resistance frequency in A. fumigatus. Our aim was to determine the resistance frequency over a period of 6 years to describe resistance phenotypes and to analyze underlying resistance mutations and trends

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